Novel NRG1 fusion bodies, fusion junctions, and methods for detecting them

Abstract

This disclosure relates to the field of neuregulin-1 (NRG1) fusions, methods for detecting such fusions, methods for identifying or diagnosing patients having such fusions, and methods for treating cancer, tumors, or abnormal cells containing NRG1 fusions. [Solution] This disclosure also relates to the field of therapeutic (human) compounds for the treatment of subjects having ErbB-2 / ErbB-3 positive cancers, including NRG1 fusions.

Description

Technical Field

[0001] The present disclosure relates to the field of neuregulin-1 (NRG1) fusion proteins, methods for detecting such fusion proteins, methods for identifying or diagnosing patients having such fusion proteins, and methods for treating cancers, tumors or abnormal cells comprising an NRG1 fusion protein. The present disclosure also relates to the field of therapeutic (human) compounds for the treatment of subjects having an ErbB-2 / ErbB-3 positive cancer comprising an NRG1 fusion protein.

Background Art

[0002] Proteolytic processing of the extracellular domain of transmembrane NRG1 isoforms releases soluble factors. HRG1-β1 is one of the proteins encoded by the NRG1 gene. NRG1 contains an Ig domain and an EGF-like domain required for direct binding to the receptor tyrosine kinases ErbB-3 and ErbB-4. The NRG1 gene and isoforms are known under several different aliases as follows: neuregulin 1, Pro-NRG1, HRGA, SMDF, HGL, GGF, NDF, NRG1 intronic transcript 2 (non-protein coding), heregulin, alpha (45kD, ERBB2 P185-activator), acetylcholine receptor inducing activity, Pro-neuregulin-1, membrane-bound isoform, sensory and motor neuron-derived factor, Neu differentiation factor, glial growth factor 2, NRG1-IT2, MSTP131, MST131, ARIA, GGF2, HRG1, and HRG. The external Ids for the NRG1 gene are HGNC:7997, Entrez Gene:3084, Ensembl:ENSG00000157168, OMIM:142445 and UniProtKB:Q02297.

[0003] NRG1 isoforms are generated by alternative splicing and include transmembrane, outer membrane-bound, detached, secreted, or intracellular forms (see Exp Cell Res 284:14-30, 2003; Hayes and Gullick in J. Mammary Gland Biol Neoplasia 13:205-214, 2008). They bind to ErbB-3 or ErbB-4, which is understood to promote heterodimerization by ErbB-2 (HER2). While NRG1-coding proteins are usually considered mitogens, they can also be potently pro-apoptotic: in particular, intracellular expression of NRG1 can induce apoptosis in expressing cells (see Weinstein et al. in oncogene 17:2107-2113, 1998).

[0004] Given the diverse sequences of tumor types containing NRG1 fusions, there is a need for faster and more stable diagnosis, and a need to identify previously unknown NRG1 fusions based on novel fusion partners and new fracture points between NRG1 and its fusion partner. [Overview of the Initiative]

[0005] This disclosure generally provides fusions comprising NRG1 and a novel fusion partner, and polypeptide fusions encoded therefrom. This disclosure provides fusions comprising NRG1 and VAPB, NRG1 and PVALB, NRG1 and DAAM1, NRG1 and ASPH, NRG1 and ZFAT, or NRG1 and DSCAML1 as novel fusion partners, which are referred to herein as VAPB-NRG1, PVALB-NRG1, DAAM1-NRG1, ASPH-NRG1, ZFAT-NRG1, and DSCAML1-NRG1, respectively, in general terms. More specifically, this aspect of this disclosure is: A VAPB nucleic acid sequence fused with an NRG1 nucleic acid sequence or a portion of an NRG1 nucleic acid sequence, or a polynucleotide containing a portion of a VAPB nucleic acid sequence, or A PVALB nucleic acid sequence fused with an NRG1 nucleic acid sequence or a portion of an NRG1 nucleic acid sequence, or a polynucleotide containing a portion of a PVALB nucleic acid sequence, or A DAAM1 nucleic acid sequence fused with an NRG1 nucleic acid sequence or a portion of an NRG1 nucleic acid sequence, or a polynucleotide containing a portion of a DAAM1 nucleic acid sequence, or An ASPH nucleic acid sequence fused with an NRG1 nucleic acid sequence or a portion of an NRG1 nucleic acid sequence, or a polynucleotide containing a portion of an ASPH nucleic acid sequence, A ZFAT nucleic acid sequence fused with an NRG1 nucleic acid sequence or a portion of an NRG1 nucleic acid sequence, or a polynucleotide containing a portion of a ZFAT nucleic acid sequence, or This relates to a DSCAML1 nucleic acid sequence fused with an NRG1 nucleic acid sequence or a portion of an NRG1 nucleic acid sequence, or to a polynucleotide containing a portion of a DSCAML1 nucleic acid sequence.

[0006] Preferably, the VAPB nucleic acid sequence contains or consists of one of the sequences of SEQ ID NOs. 17 to 23, or a part of an allele variant of one of the sequences of SEQ ID NOs. 23. Preferably, the NRG1 nucleic acid sequence contains or consists of one of the sequences of SEQ ID NOs. 125 to 138, or a part of an allele variant of one of the sequences of SEQ ID NOs. 125 to 138.

[0007] Alternatively or additionally, the Disclosure provides polynucleotides comprising a portion of exon 1 of VAPB, or a portion of an allele variant of exon 1, fused with a portion of exon 2 of NRG1, or a portion of an allele variant of exon 2. Preferably, exon 1 of VAPB comprises or consists of SEQ ID NO: 17, and the allele variant is preferably a variant of SEQ ID NO: 17. Preferably, exon 2 of NRG1 comprises or consists of SEQ ID NO: 126, and the allele variant is preferably a variant of SEQ ID NO: 126.

[0008] Preferably, the PVALB nucleic acid sequence contains or consists of one of the sequences of SEQ ID NOs. 439 to 444, or a portion of an allele variant of one of the sequences of SEQ ID NOs. Preferably, the NRG1 nucleic acid sequence contains or consists of one of the sequences of SEQ ID NOs. 125 to 138, or a portion of an allele variant of one of the sequences of SEQ ID NOs. 125 to 138.

[0009] Alternatively or additionally, the Disclosure provides polynucleotides comprising a portion of exon 4 of PVALB, or a portion of an allele variant of exon 4, fused with a portion of exon 6 of NRG1, or a portion of an allele variant of exon 6. Preferably, exon 4 of PVALB comprises or consists of SEQ ID NO: 442, and the allele variant is preferably a variant of SEQ ID NO: 442. Exon 6 of NRG1 preferably comprises or consists of SEQ ID NO: 130, and the allele variant is preferably a variant of SEQ ID NO: 130.

[0010] Preferably, the DAAM1 nucleic acid sequence contains or consists of one of the sequences of SEQ ID NOs. 606 to 631, or a portion of an allele variant of one of the sequences of SEQ ID NOs. Preferably, the NRG1 nucleic acid sequence contains or consists of one of the sequences of SEQ ID NOs. 125 to 138, or a portion of an allele variant of one of the sequences of SEQ ID NOs. 125 to 138.

[0011] Alternatively or additionally, the Disclosure provides polynucleotides comprising a portion of exon 1 of DAAM1, or a portion of an allele variant of exon 1, fused with a portion of exon 1 of NRG1, or a portion of an allele variant of exon 1. Preferably, exon 1 of DAAM1 comprises or consists of SEQ ID NO: 606, and the allele variant is preferably a variant of SEQ ID NO: 606. Preferably, exon 1 of NRG1 comprises or consists of SEQ ID NO: 125, and the allele variant is preferably a variant of SEQ ID NO: 125.

[0012] Preferably, the ASPH nucleic acid sequence includes or consists of one of the sequences of SEQ ID NOs. 637 to 662, or a part of one allele variant of one of SEQ ID NOs. Preferably, the NRG1 nucleic acid sequence includes or consists of one of the sequences of SEQ ID NOs. 125 to 138, or a part of one allele variant of one of SEQ ID NOs. 125 to 138.

[0013] Alternatively or additionally, the Disclosure provides polynucleotides comprising a portion of exon 22 of ASPH, or a portion of an allele variant of exon 22, fused with a portion of exon 2 of NRG1, or a portion of an allele variant of exon 2. Preferably, exon 22 of ASPH comprises or consists of SEQ ID NO: 658, and the allele variant is preferably a variant of SEQ ID NO: 658. Preferably, exon 2 of NRG1 comprises or consists of SEQ ID NO: 126, and the allele variant is preferably a variant of SEQ ID NO: 126.

[0014] Preferably, the ZFAT nucleic acid sequence contains or consists of one of the sequences of SEQ ID NOs. 830 to 846, or a portion of an allele variant of one of the sequences of SEQ ID NOs. Preferably, the NRG1 nucleic acid sequence contains or consists of one of the sequences of SEQ ID NOs. 125 to 138, or a portion of an allele variant of one of the sequences of SEQ ID NOs. 125 to 138.

[0015] Alternatively or additionally, the Disclosure provides polynucleotides comprising a portion of exon 12 of ZFAT, or a portion of an allele variant of exon 12, fused with a portion of exon 6 of NRG1, or a portion of an allele variant of exon 6. Preferably, exon 12 of ZFAT comprises or consists of SEQ ID NO: 841, and the allele variant is preferably a variant of SEQ ID NO: 841. Exon 6 of NRG1 preferably comprises or consists of SEQ ID NO: 130, and the allele variant is preferably a variant of SEQ ID NO: 130.

[0016] Preferably, the DSCAML1 nucleic acid sequence contains or consists of one of the sequences of SEQ ID NOs. 870 to 903, or a portion of an allele variant of one of the sequences of SEQ ID NOs. Preferably, the NRG1 nucleic acid sequence contains or consists of one of the sequences of SEQ ID NOs. 125 to 138, or a portion of a allele variant of one of the sequences of SEQ ID NOs. 125 to 138.

[0017] Alternatively or additionally, the Disclosure provides polynucleotides comprising a portion of exon 3 of DSCAML1, or a portion of an allele variant of exon 3, fused with a portion of exon 2 of NRG1, or a portion of an allele variant of exon 2. Preferably, exon 3 of DSCAML1 comprises or consists of SEQ ID NO: 872, and the allele variant is preferably a variant of SEQ ID NO: 872. Preferably, exon 2 of NRG1 comprises or consists of SEQ ID NO: 126, and the allele variant is preferably a variant of SEQ ID NO: 126.

[0018] In addition, this disclosure provides a fusion comprising NRG1 having a previously undisclosed fusion junction, and a polypeptide fusion encoded therefrom.In particular, this disclosure further provides a fusion comprising NRG1 and CADM1, which is referred to herein as CADM1-NRG1 in general terms; this disclosure also provides a fusion comprising NRG1 and CD44, which is referred to herein as CD44-NRG1 in general terms; this disclosure provides a fusion comprising NRG1 and SLC3A2, which is referred to herein as SLC3A2-NRG1 in general terms; this disclosure provides a fusion comprising NRG1 and VTCN1, which is referred to herein as VTCN1-NRG1 in general terms; this disclosure provides a fusion comprising NRG1 and VTCN1 in general terms. This disclosure provides a fusion comprising NRG1 and CDH1, which is referred to herein as CDH1-NRG1 in general terms; this disclosure provides a fusion comprising NRG1 and CXADR, which is referred to herein as CXADR-NRG1 in general terms; this disclosure provides a fusion comprising NRG1 and GTF2E2, which is referred to herein as GTF2E2-NRG1 in general terms; this disclosure provides a fusion comprising NRG1 and CSMD1, which is referred to herein as CSMD1-NRG1 in general terms; and this disclosure provides a fusion comprising PTN-NR The disclosure provides a fusion comprising NRG1 and PTN, referred to as G1; the disclosure provides a fusion comprising NRG1 and ST14, referred to herein as ST14-NRG1 in general terms; the disclosure provides a fusion comprising NRG1 and THBS1, referred to herein as THBS1-NRG1 in general terms; the disclosure provides a fusion comprising NRG1 and AGRN, referred to herein as AGRN-NRG1 in general terms; and the disclosure also provides a fusion comprising NRG1 and APP, referred to herein as APP-NRG1 in general terms. The disclosure provides a fusion, and also provides a fusion comprising NRG1 and NOTCH2, which are referred to herein as NOTCH2-NRG1 in general terms; the disclosure also provides a fusion comprising NRG1 and CD74, which are referred to herein as CD74-NRG1 in general terms; the disclosure also provides a fusion comprising NRG1 and SDC4, which are referred to herein as SDC4-NRG1 in general terms; and the disclosure also provides a fusion comprising NRG1 and SLC4A4, which are referred to herein as SLC4A4-NRG1 in general terms.

[0019] This disclosure provides the following novel fusion junctions. In particular, this disclosure provides a polynucleotide comprising a portion of exon 7 of CADM1, or a portion of an allele variant of exon 7, fused with a portion of exon 6 of NRG1, or a portion of an allele variant of exon 6. Preferably, exon 7 of CADM1 comprises or consists of SEQ ID NO: 39, and the allele variant is preferably a variant of SEQ ID NO: 39. Preferably, exon 6 of NRG1 comprises or consists of SEQ ID NO: 130, and the allele variant is preferably a variant of SEQ ID NO: 130.

[0020] In particular, this disclosure provides a polynucleotide comprising a portion of CD44 exon 5, or a portion of an allele variant of exon 5, fused with a portion of exon 2 of NRG1, or a portion of an allele variant of exon 2. Preferably, CD44 exon 5 comprises or consists of SEQ ID NO: 65, and the allele variant is preferably a variant of SEQ ID NO: 65. Preferably, NRG1 exon 2 comprises or consists of SEQ ID NO: 126, and the allele variant is preferably a variant of SEQ ID NO: 126.

[0021] In particular, this disclosure provides polynucleotides comprising a portion of CD44 exon 5, or a portion of an allele variant of exon 5, fused with a portion of exon 6 of NRG1, or a portion of an allele variant of exon 6. Preferably, CD44 exon 5 comprises or consists of SEQ ID NO: 65, and the allele variant is preferably a variant of SEQ ID NO: 65. Preferably, NRG1 exon 6 comprises or consists of SEQ ID NO: 130, and the allele variant is preferably a variant of SEQ ID NO: 130.

[0022] In particular, this disclosure provides a polynucleotide comprising exon 1 of transcription version 6 of SLC3A2, or a portion of an allele variant of exon 1 of transcription version 6, fused with a portion of exon 5 of NRG1, or a portion of an allele variant of exon 2 of NRG1. Preferably, the exon of SLC3A2 comprises or consists of SEQ ID NO: 103, and the allele variant is preferably a variant of SEQ ID NO: 103. Preferably, exon 5 of NRG1 comprises or consists of SEQ ID NO: 129, and the allele variant is preferably a variant of SEQ ID NO: 129.

[0023] In particular, this disclosure provides polynucleotides comprising a portion of exon 2 of VTCN1 or a portion of an allele variant of exon 2 fused with a portion of exon 2 of NRG1 or an allele variant of exon 2. Preferably, exon 2 of VTCN1 contains or consists of SEQ ID NO: 169, and the allele variant is preferably a variant of SEQ ID NO: 169. Preferably, exon 2 of NRG1 contains or consists of SEQ ID NO: 126, and the allele variant is preferably a variant of SEQ ID NO: 126.

[0024] In particular, this disclosure provides a polynucleotide comprising a portion of CDH1 exon 11, or a portion of an allele variant of exon 11, fused with a portion of exon 2 of NRG1, or a portion of an allele variant of exon 2. Preferably, CDH1 exon 11 comprises or consists of SEQ ID NO: 198, and the allele variant is preferably a variant of SEQ ID NO: 198. Preferably, NRG1 exon 2 comprises or consists of SEQ ID NO: 126, and the allele variant is preferably a variant of SEQ ID NO: 126.

[0025] In particular, the present disclosure provides a polynucleotide comprising exon 1 of CXADR, or a portion of an allelic variant of exon 1, fused to exon 2 of NRG1, or a portion of an allelic variant of exon 2. Preferably, exon 1 of CXADR comprises or consists of SEQ ID NO: 219, and the allelic variant is preferably a variant of SEQ ID NO: 219. Exon 2 of NRG1 preferably comprises or consists of SEQ ID NO: 126, and the allelic variant is preferably a variant of SEQ ID NO: 126.

[0026] In particular, the present disclosure provides a polynucleotide comprising exon 2 of GTF2E2, or a portion of an allelic variant of exon 2, fused to exon 2 of NRG1, or a portion of an allelic variant of exon 2. Preferably, exon 2 of GTF2E2 comprises or consists of SEQ ID NO: 236, and the allelic variant is preferably a variant of SEQ ID NO: 236. Exon 2 of NRG1 preferably comprises or consists of SEQ ID NO: 126, and the allelic variant is preferably a variant of SEQ ID NO: 126.

[0027] In particular, the present disclosure provides a polynucleotide comprising exon 23 of CSMD1, or a portion of an allelic variant of exon 23, fused to exon 6 of NRG1, or a portion of an allelic variant of exon 6. Preferably, exon 23 of CSMD1 comprises or consists of SEQ ID NO: 279, and the allelic variant is preferably a variant of SEQ ID NO: 279. Exon 6 of NRG1 preferably comprises or consists of SEQ ID NO: 130, and the allelic variant is preferably a variant of SEQ ID NO: 130.

[0028] In particular, this disclosure provides a polynucleotide comprising a portion of exon 4 of PTN, or a portion of an allele variant of exon 4, fused with a portion of exon 2 of NRG1, or a portion of an allele variant of exon 2. Preferably, exon 4 of PTN comprises or consists of SEQ ID NO: 318, and the allele variant is preferably a variant of SEQ ID NO: 318. Preferably, exon 2 of NRG1 comprises or consists of SEQ ID NO: 126, and the allele variant is preferably a variant of SEQ ID NO: 126.

[0029] In particular, this disclosure provides a polynucleotide comprising a portion of exon 11 of ST14, or a portion of an allele variant of exon 11, fused with a portion of exon 6 of NRG1, or a portion of an allele variant of exon 6. Preferably, exon 11 of ST14 comprises or consists of SEQ ID NO: 342, and the allele variant is preferably a variant of SEQ ID NO: 342. Preferably, exon 6 of NRG1 comprises or consists of SEQ ID NO: 130, and the allele variant is preferably a variant of SEQ ID NO: 130.

[0030] In particular, this disclosure provides a polynucleotide comprising a portion of exon 9 of THBS1, or a portion of an allele variant of exon 9, fused with a portion of exon 6 of NRG1, or a portion of an allele variant of exon 6. Preferably, exon 9 of THBS1 comprises or consists of SEQ ID NO: 386, and the allele variant is preferably a variant of SEQ ID NO: 386. Preferably, exon 6 of NRG1 comprises or consists of SEQ ID NO: 130, and the allele variant is preferably a variant of SEQ ID NO: 130.

[0031] In particular, this disclosure provides a polynucleotide comprising a portion of exon 12 of AGRN, or a portion of an allele variant of exon 12, fused with a portion of exon 6 of NRG1, or a portion of an allele variant of exon 6. Preferably, exon 12 of AGRN comprises or consists of SEQ ID NO: 416, and the allele variant is preferably a variant of SEQ ID NO: 416. Preferably, exon 6 of NRG1 comprises or consists of SEQ ID NO: 130, and the allele variant is preferably a variant of SEQ ID NO: 130.

[0032] In particular, this disclosure provides a polynucleotide comprising a portion of exon 4 of PVALB, or a portion of an allele variant of exon 4, fused with a portion of exon 6 of NRG1, or a portion of an allele variant of exon 6. Preferably, exon 4 of PVALB comprises or consists of SEQ ID NO: 442, and the allele variant is preferably a variant of SEQ ID NO: 442. Preferably, exon 6 of NRG1 comprises or consists of SEQ ID NO: 130, and the allele variant is preferably a variant of SEQ ID NO: 130.

[0033] In particular, this disclosure provides a polynucleotide comprising exon 2 of transcription version 3 of SLC3A2, or a portion of an allele variant of exon 2 of transcription version 3, fused with exon 6 of NRG1, or a portion of an allele variant of exon 6. Preferably, the exon of SLC3A2 comprises or consists of SEQ ID NO: 457, and the allele variant is preferably a variant of SEQ ID NO: 457. Preferably, exon 6 of NRG1 comprises or consists of SEQ ID NO: 130, and the allele variant is preferably a variant of SEQ ID NO: 130.

[0034] In particular, this disclosure provides a polynucleotide comprising a portion of exon 14 of APP, or a portion of an allele variant of exon 14, fused with a portion of exon 6 of NRG1, or a portion of an allele variant of exon 6. Preferably, exon 14 of APP comprises or consists of SEQ ID NO: 501, and the allele variant is preferably a variant of SEQ ID NO: 501. Preferably, exon 6 of NRG1 comprises or consists of SEQ ID NO: 130, and the allele variant is preferably a variant of SEQ ID NO: 130.

[0035] In particular, this disclosure provides a polynucleotide comprising a portion of exon 33 of WRN, or a portion of an allele variant of exon 33, fused with a portion of exon 6 of NRG1, or a portion of an allele variant of exon 6. Preferably, exon 33 of WRN comprises or consists of SEQ ID NO: 562, and the allele variant is preferably a variant of SEQ ID NO: 562. Preferably, exon 6 of NRG1 comprises or consists of SEQ ID NO: 130, and the allele variant is preferably a variant of SEQ ID NO: 130.

[0036] In particular, this disclosure provides polynucleotides comprising exon 6 of NOTCH2, or a portion of an allele variant of exon 6, fused with exon 6 of NRG1, or a portion of an allele variant of exon 6. Preferably, exon 6 of NOTCH2 comprises or consists of SEQ ID NO: 700, and the allele variant is preferably a variant of SEQ ID NO: 700. Preferably, exon 6 of NRG1 comprises or consists of SEQ ID NO: 130, and the allele variant is preferably a variant of SEQ ID NO: 130.

[0037] In particular, this disclosure provides polynucleotides comprising a portion of CD74 exon 2 or a portion of an allele variant of exon 2 fused with a portion of exon 2 of NRG1 or an allele variant of exon 2. Preferably, the CD74 exon 2 comprises or consists of SEQ ID NO: 720, and the allele variant is preferably a variant of SEQ ID NO: 720. Preferably, the NRG1 exon 2 comprises or consists of SEQ ID NO: 126, and the allele variant is preferably a variant of SEQ ID NO: 126.

[0038] In particular, this disclosure provides polynucleotides comprising a portion of exon 2 of SDC4 or a portion of an allele variant of exon 2 fused with a portion of exon 2 of NRG1 or an allele variant of exon 2. Preferably, exon 2 of SDC4 comprises or consists of SEQ ID NO: 746, and the allele variant is preferably a variant of SEQ ID NO: 746. Preferably, exon 2 of NRG1 comprises or consists of SEQ ID NO: 126, and the allele variant is preferably a variant of SEQ ID NO: 126.

[0039] In particular, this disclosure provides a polynucleotide comprising exon 4 of SDC4, or a portion of an allele variant of exon 4, fused with exon 2 of NRG1, or a portion of an allele variant of exon 2. Preferably, exon 4 of SDC4 comprises or consists of SEQ ID NO: 748, and the allele variant is preferably a variant of SEQ ID NO: 748. Preferably, exon 2 of NRG1 comprises or consists of SEQ ID NO: 126, and the allele variant is preferably a variant of SEQ ID NO: 126.

[0040] In particular, this disclosure provides a polynucleotide comprising exon 14 of SLC4A4, or a portion of an allele variant of exon 14, fused with exon 6 of NRG1, or a portion of an allele variant of exon 6. Preferably, exon 14 of SLC4A4 contains or consists of SEQ ID NO: 780, and the allele variant is preferably a variant of SEQ ID NO: 780. Preferably, exon 6 of NRG1 contains or consists of SEQ ID NO: 130, and the allele variant is preferably a variant of SEQ ID NO: 130.

[0041] All NRG1 fusions provided herein have been observed in patient-derived samples, specifically in patients diagnosed with cancer.

[0042] The disclosed identification of these NRG1 fusions and gene rearrangements provides novel methods for determining the presence of NRG1 polynucleotide fusions or polypeptides in or from biological samples, methods for assaying the activity of NRG1 polypeptide fusions, methods for diagnosing cancers, tumors or abnormal cells expressing NRG1 polypeptide fusions, and methods for treating cancers, tumors or abnormal cells expressing NRG1 polypeptide fusions, and / or inhibiting the progression of cancer characterized by the expression of NRG1 polynucleotide fusions or polypeptides. Accordingly, these and more embodiments are also provided by this disclosure and are described in more detail below.

[0043] This disclosure also provides polypeptide fusions encoded by any one of the polynucleotide fusions selected from VAPB-NRG1, CADM1-NRG1, CD44-NRG1, SLC3A2-NRG1, VTCN1-NRG1, CDH1-NRG1, CXADR-NRG1, GTF2E2-NRG1, CSMD1-NRG1, PTN-NRG1, ST14-NRG1, THBS1-NRG1, AGRN-NRG1, PVALB-NRG1, APP-NRG1, WRN-NRG1, ASPH-NRG1, NOTCH2-NRG1, CD74-NRG1, SDC4-NRG1, SLC4A4-NRG1, ZFAT-NRG1, and DSCAML1-NRG1. Any one of the polypeptide fusions of this disclosure preferably also includes the EGF-like domain of NRG1 when expressed by the abnormal cells described herein. Any polynucleotide fusion of the present disclosure, when contained in the abnormal cells described herein, preferably comprises an EGF-like domain, for example, exon 6, 7, or 8 of NRG1, more preferably an NRG1 exon encoding exons 6 and 7 of the NRG1 polynucleotide sequence.

[0044] Also provided are vectors comprising the polynucleotide fusion of the Disclosure, and recombinant host cells comprising the polynucleotide and / or the vector. Also provided are methods for producing the polypeptide of the Disclosure, comprising maintaining the recombinant host cell under conditions suitable for the expression of the polynucleotide, thereby expressing the polynucleotide fusion, producing the polypeptide fusion, and subsequently isolating or purifying the polypeptide. Also provided are methods for producing recombinant host cells, comprising introducing the vector into host cells.

[0045] Also provided are nucleic acid probes, primers, or primer pairs for detecting the polynucleotide fusions of the Disclosure, and detection assays comprising nucleic acid probes, primers, or primer pairs for detecting the presence of the polynucleotide fusions of the Disclosure. Such nucleic acid probes, primers, or primer pairs of the Disclosure have a preferred length of 10 to 40 nucleotides.

[0046] Also provided are a detection assay comprising a first antibody, or a set of the first antibody and a second antibody, for detecting a polypeptide encoded by the polynucleotide fusion of the present disclosure, and a detection assay comprising a first antibody, or a set of the first antibody and a second antibody, for detecting the presence of a polypeptide encoded by the polynucleotide fusion of the present disclosure. Preferably, the first antibody is conjugated to a polypeptide fusion selected from VAPB-NRG1, CADM1-NRG1, CD44-NRG1, SLC3A2-NRG1, VTCN1-NRG1, CDH1-NRG1, CXADR-NRG1, GTF2E2-NRG1, CSMD1-NRG1, PTN-NRG1, ST14-NRG1, THBS1-NRG1, AGRN-NRG1, PVALB-NRG1, APP-NRG1, WRN-NRG1, ASPH-NRG1, NOTCH2-NRG1, CD74-NRG1, SDC4-NRG1, SLC4A4-NRG1, ZFAT-NRG1 and DSCAML1-NRG1, and the first and second antibody sets are conjugated to VAPB and It connects to NRG1, or CADM1 and NRG1, or CD44 and NRG1, or SLC3A2 and NRG1, or VTCN1 and NRG1, or CDH1 and NRG1, or CXADR and NRG1, or GTF2E2 and NRG1, or CSMD1 and NRG1, or PTN and NRG1, or ST14 and NRG1, or THBS1 and NRG1, or AGRN and NRG1, or PVALB and NRG1, APP and NRG1, or WRN and NRG1, or ASPH and NRG1, or NOTCH2 and NRG1, or CD74 and NRG1, or SDC4 and NRG1, or SLC4A4 and NRG1, or ZFAT and NRG1, or DSCAML1 and NRG1.

[0047] This disclosure, including methods for identifying or detecting NRG1 fusions in human subjects, further encompasses diagnostic, therapeutic selection, and therapeutic methods, including those for the treatment of NRG1 fusion-related diseases, including solid tumors, using drugs and combinations thereof. In particular, this disclosure provides simple means or assays for rapidly assessing whether a subject is affected or susceptible to cancer, tumors, or abnormal cells. Such NRG1 fusion information can advantageously be used as a biomarker in diagnostic tools.

[0048] Accordingly, a method is also provided for identifying in a sample any one of the polynucleotide fusions referred to herein, or polypeptides encoded therefrom, the method comprising testing a sample obtained from a subject to detect the presence of the fusion in the sample.

[0049] Also provided is a method for detecting the presence of any one of the polynucleotide fusions or polypeptides encoded therefrom in a sample, the method comprising testing a sample obtained from a subject and detecting the presence of the fusion in the sample.

[0050] Furthermore, a method is provided for determining whether abnormal cells, such as cancer cells or tumor cells, derived from a subject contain any one of the polynucleotide fusions described herein or polypeptides encoded therefrom, the method comprising testing cells obtained from the subject, or the polynucleotide or polypeptide content of said cells, for the presence of fusions in a sample.

[0051] Also provided is a method for identifying a subject having any one of the polynucleotide fusions referred to herein or polypeptides encoded thereby, the method comprising testing a sample obtained from the subject and detecting the presence of the fusion in the sample.

[0052] The testing of the samples described herein is preferably in vitro analysis or a similar method, or ex vivo analysis or a part of such a method.

[0053] Preferably, the subject is a mammal or a human subject, and the polynucleotide or polypeptide is a mammal or human polynucleotide or polypeptide.

[0054] Preferably, any polynucleotide fusion described herein and / or polypeptide encoded therefrom described herein are isolated and / or purified, or substantially isolated or substantially purified.

[0055] This disclosure relates to subjects who have or are suspected of having cancer, particularly solid cancers or tumors. In particular, such cancers include adenocarcinoma, more specifically mucinous adenocarcinoma; pancreatic cancer, more specifically pancreatic adenocarcinoma; or renal cell carcinoma, cholangiocarcinoma, brain cancer, glioblastoma, cholangiocarcinoma, glioma, pancreatic ductal adenocarcinoma, sarcoma, bladder cancer, colon cancer, rectal cancer, colorectal cancer, gallbladder cancer, head and neck cancer, prostate cancer, uterine cancer, breast cancer, ovarian cancer, liver cancer, endometrial cancer, lung cancer, particularly non-small cell lung cancer, or invasive mucinous adenocarcinoma. The cancer may be primary or metastatic.

[0056] This disclosure also provides a method for treating subjects having ErbB-2 and / or ErbB-3 positive abnormal cells, such as cancer or tumors, wherein such abnormal cells include cells expressing polynucleotide fusions and / or polypeptide fusions encoded thereby, and the method comprises administering a therapeutic dose of an ErbB-2 and / or ErbB-3 targeting agent to the subject. Preferably, the administration of the agent is performed after detection of the polynucleotide or polypeptide fusions described herein.

[0057] This disclosure also provides a method for inhibiting progression in subjects having ErbB-2 and ErbB-3 positive abnormal cells, wherein the abnormal cells express polynucleotide fusions and / or polypeptide fusions encoded thereby, and the method comprises administering a therapeutic dose of an ErbB-2 and / or ErbB-3 targeting agent to the subject. Preferably, the administration of the agent is performed after detection of the polynucleotide or polypeptide fusions described herein.

[0058] This disclosure also provides ErbB-2 and / or ErbB-3 targeting agents for use in the treatment of subjects having ErbB-2 and ErbB-3 positive cancer or tumors, which express polynucleotide fusions and / or polypeptide fusions encoded thereby, the treatment comprising administering a therapeutic dose of the ErbB-2 and / or ErbB-3 targeting agent to the subject. Preferably, the administration of the agent is performed after detection of the polynucleotide or polypeptide fusions described herein.

[0059] This disclosure also provides a method for diagnosing a subject having abnormal cells containing a polynucleotide fusion as described herein, or a polypeptide encoded thereby, the method comprising testing a sample obtained from the subject to detect the presence of the fusion in the sample.

[0060] This disclosure also provides a method of treatment or use of ERB2 and / or Erb3 targeting agents, wherein the subject is screened for the presence of the NRG1 fusion described herein, followed by administration of the Erb2 and / or Erb3 agent.

[0061] This disclosure also includes in vivo models such as xenografts or transgenic animal models expressing polynucleotide fusions and / or polypeptide fusions encoded thereby in their genomes or in cells with abnormal engraftment, and treatment of such models with such agents for evaluating the therapeutic activity of ERB2 and / or Erb3 targeters or other targeters. Preferably, the animal model is a non-human animal model. [Modes for carrying out the invention]

[0062] This disclosure provides fusions comprising NRG1 and a novel fusion partner, as well as polypeptide fusions encoded therefrom. Furthermore, this disclosure provides fusions comprising NRG1 having a previously undisclosed fusion junction, and polypeptide fusions encoded therefrom.

[0063] Generally, this disclosure provides a fusion body comprising NRG1 and a fusion partner selected from VAPB, CADM1, CD44, SLC3A2, VTCN1, CDH1, CXADR, GTF2E2, CSMD1, PTN, ST14, THBS1, AGRN, PVALB, APP, WRN, DAAM1, ASPH, NOTCH2, CD74, SDC4, SLC4A4, ZFAT, or DSCAML1. The fusion is referred to herein as VAPB-NRG1, CADM1-NRG1, CD44-NRG1, SLC3A2-NRG1, VTCN1-NRG1, CDH1-NRG1, CXADR-NRG1, GTF2E2-NRG1, CSMD1-NRG1, PTN-NRG1, ST14-NRG1, THBS1-NRG1, AGRN-NRG1, PVALB-NRG1, APP-NRG1, WRN-NRG1, DAAM1-NRG1, ASPH-NRG1, NOTCH2-NRG1, CD74-NRG1, SDC4-NRG1, SLC4A4-NRG1, ZFAT-NRG1, or DSCAML1-NRG1. The presence of any one of the NRG1 fusions of this disclosure, whether it is a polynucleotide or a polypeptide translated therefrom, indicates the presence of abnormal cells such as cancer or tumors.

[0064] NRG1 The NRG1 gene encodes various isoforms of NRG1. These various isoforms and their expected functions are described in Adelaide et al. Genes Chromosomes Cancer, Aug;37(4):333-45 (2003). The GGF and GGF2 isoforms contain a Kringle-like sequence plus Ig and EGF-like domains, while the SMDF isoform shares only the EGF-like domain with the other isoforms. The receptor for the NRG1 isoform is the ErbB family of tyrosine kinase transmembrane receptors. This family is also known as the human epidermal growth factor (EGF) receptor family (HER). The family has four members: ErbB(erythroblastoma)-1, ErbB-2, ErbB-3, and ErbB-4. The receptors (reviewed in Yarden and Pines, Nat Rev Cancer. 2012 Jul 12;12(8):553-63) are widely expressed on epithelial cells. Upregulation of HER receptors or their ligands, such as heregulin (HRG) or epidermal growth factor (EGF), is a frequent event in human cancers (Wilson, Fridlyand et al., Nature. 2012 Jul 26;487(7408):505-509). In particular, overexpression of ErbB-1 and ErbB-2 occurs in epithelial tumors and is associated with tumor invasion, metastasis, resistance to chemotherapy, and poor prognosis (Zhang, H., Berezov, A., Wang, Q., Zhang, G., Drebin, J., Murali, R., et al. (2007) Erbb receptors: from oncogenes to targeted cancer therapies. J. Clin. Invest., 117, 2051-2058). In normal breast tissue, ErbB-3 has been shown to be important for the growth and differentiation of luminal epithelium. For example, loss / inhibition of ErbB-3 leads to selective basal expansion on the luminal epithelium (Balko, Miller et al., 2012 PNAS January 3, 2012 109(1)221-226).Ligand binding to the extracellular domain of receptor tyrosine kinases induces receptor dimerization of both the same (homodimerization) and different (heterodimerization) receptor subtypes. Dimerization can activate the intracellular tyrosine kinase domain, which can then undergo autophosphorylation and subsequently activate several downstream proliferative signaling pathways, including those mediated by mitogen-activated protein kinase (MAPK) and the proliferative pathway Akt (reviewed in Yarden and Pines, 2012). ErbB-3 can be activated by its ligand engagement. These ligands include, but are not limited to, neuregulin (NRG) and heregulin (HRG) and NRG1 fusions.

[0065] Various NRG1 fusion genes are described in Dhanasekaran et al. Nature Communications 5:5893,2014 and Jonna et al., Clin Cancer Res August 15 2019,25(16)4966-4972.

[0066] As used herein, the term "NRG1" is not intended to be limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but is intended to include all such forms unless the context explicitly indicates which form is intended. The NRG1 gene and isoforms are known under several different aliases, including: neuregulin-1, Pro-NRG1, HRGA, SMDF, HGL, GGF, NDF, NRG1 intronic transcript 2 (non-protein coded), heregulin, alpha (45kD, ERBB2 P185-activator), acetylcholine receptor-inducing activity, Pro-neuregulin-1, membrane-bound isoform, sensory and motor neuron-derived factor, Neu differentiation factor, glial growth factor 2, NRG1-IT2, MSTP131, MST131, ARIA, GGF2, HRG1, and HRG. The external IDs for the NRG1 gene are HGNC:7997, Entrez Gene:3084, Ensembl:ENSG00000157168, OMIM:142445, and UniProtKB:Q02297. To avoid misunderstanding, the NRG1 sequence means any polynucleotide sequence containing any exon, but also any polypeptide sequence or any portion thereof, such as the NCBI reference sequence NM_001159999.3 or an allele variant of NM_001159999.3. Preferably, the entire polynucleotide sequence of the NRG1 of this disclosure to be transcribed follows SEQ ID NO: 138, and the translated NRG1 polypeptide sequence follows SEQ ID NO: 152.

[0067] Preferably, a portion of the NRG1 protein sequence, or a polynucleotide fusion encoding an exon of NRG1, further comprises or encodes the EGF-like domain of NRG1. The NRG1 gene in the fusion, for example, the 3' end of the NRG1 gene, preferably contains the coding sequence of exons 6, 7, or 8. This domain is encoded by a portion located at 3' of the NRG1 gene (e.g., exons 6-8) and is required for binding to ErbB-3. The NRG1 fusion gene preferably comprises a nucleic acid sequence encoding the EGF-like domain of NRG1. The NRG1 fusion of this disclosure preferably retains the in-frame coding region of this EGF-like domain at the 3' end of the fusion molecule. EGF-like domains are typically sequences of approximately 30–40 amino acid residues, the prototype of which is found in the sequence of epidermal growth factor (EGF) [PMID:2288911, PMID:6334307, PMID:1522591, PMID:6607417, PMID:3282918, PMID:11498013]. They are known to be present in a number of other, mainly animal, proteins, in more or less conserved forms. A common feature of EGF-like domains is that they are found in the extracellular domains of membrane-bound proteins or in proteins known to be secreted (exception: prostaglandin G / H synthase). EGF domains typically contain six cysteine ​​residues, which have been shown to be involved in disulfide bonding (in EGF). The main structure is a double-stranded beta sheet followed by a loop to a short double-stranded sheet at the C-terminus. Conserved subdomains between cysteines differ in length. The exemplary EGF-like domains of this disclosure are preferably comprised of exons 6-8, more preferably 6 and 7, of the NCBI reference sequence NM_001159999.3, but this disclosure relates to any functional EGF-like domain of NRG1.Therefore, the EGF-like domain of NRG1 preferably includes the exemplary sequence HLVKCAEKEKTFCVNGGECFMVKDLSNPSRYLCKCPNEFTGDRCQNYVMASF (SEQ ID NO: 163), or allele variants thereof having at least 85% identity thereto, or at least 90%, 92%, 94%, 95%, 96%, or even at least 98% identity thereto.

[0068] Any NRG1-fusion polynucleotide of this disclosure preferably includes at least the 5' portion of VAPB, CADM1, CD44, SLC3A2, VTCN1, CDH1, CXADR, GTF2E2, CSMD1, PTN, ST14, THBS1, AGRN, PVALB, APP, WRN, DAAM1, ASPH, NOTCH2, CD74, SDC4, SLC4A4, ZFAT, or DSCAML1 as a fusion partner fused to the 3' portion of the NRG1 nucleic acid sequence. The translated polypeptide fusion includes a free C-terminus of the NRG1-fusion polypeptide and a free N-terminus of the fusion partner. To reflect this orientation at the molecular fusion level, any fusion partner of NRG1 is referred to first, followed by NRG1 being referred to as its fusion partner.

[0069] VAPB VAPB, or vesicle-associated membrane protein-associated protein B / C, is known by several different names, including VAMP-associated protein B and C, VAMP (vesicle-associated membrane protein)-associated protein B and C, VAP-B, VAPB, ALS8, VAMP-associated 33kDa protein, VAMP-associated protein B / C, VAMP-B / VAMP-C, VAP-B / VAP-C, VAMP-B and VAP-C. The external IDs for the VAPB gene are HGNC:12649, Entrez Gene:9217, Ensembl:ENSG00000124164, OMIM:605704, and UniProtKB:O95292. As used herein, the term "VAPB" is not intended to be limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but is intended to include all such forms unless the context explicitly indicates which form is intended. To avoid misunderstanding, a VAPB sequence means any polynucleotide sequence containing a coding sequence or any exon, but also any polypeptide sequence or any part thereof, such as the NCBI reference sequence NM_004738.4 or any allele variant thereof.

[0070] CADM1 CADM1, or cell adhesion molecule 1, is known by several different names in lung cancer, including tumor suppressor 1, TSLC1, TSLC-1, spermatogenic immunoglobulin superfamily, SgIgSF, SgIGSF, immunoglobulin superfamily member 4, IGSF4, IgSF4, IGSF4A, synaptic cell adhesion molecule, SynCAM1, SYNCAM1, SynCAM, SYNCAM, nectin-like protein 2, NECL2, NECL-2, nectin-like 2, Necl-2, RA175, ST17, BL2, immunoglobulin superfamily, member 4D variant 1, immunoglobulin superfamily, member 4D variant 2, immunoglobulin superfamily, member 4, TSLC1 / nectin-like 2 / IGSF4, cleaved CADM1 protein, and STSLC-1. The external IDs for CADM1 are HGNC:5951, Entrez Gene:23705, Ensembl:ENSG00000182985, OMIM:605686, and UniProtKB:Q9BY67. As used herein, the term "CADM1" is not intended to be limited to any form such as a protein, RNA, mRNA, cDNA, or DNA sequence, but is intended to include all such forms unless the context specifies the form of the subject to be intended. To avoid misunderstanding, a CADM1 sequence means any polynucleotide sequence containing a coding sequence or any exon, but also means any polypeptide sequence or any part thereof, such as the NCBI reference sequence NM_001301045.1 or any allele variant thereof.

[0071] CD44 CD44 is known by several different names, including CD44 molecule (Indian blood group), hematopoietic cell E- and L-selectin ligand, GP90 lymphocyte homing / adhesion receptor, chondroitin sulfate proteoglycan 8, extracellular matrix receptor III, heparan sulfate proteoglycan, phagocyte glycoprotein 1, hyaluronic acid receptor, Hermes antigen, CD44 antigen, ECMR-III, HUTCH-I, epican, MDU2, MDU3, MIC4, LHR, CD44 antigen (homing function and Indian blood group system), homing function and Indian blood group system, cell surface glycoprotein CD44, Indian blood group antigen, phagocyte glycoprotein I, soluble CD44, CDW44, CSPG8, HCELL, CDw44, PGP-1, MC56, Pgp1, and IN. The external IDs for the CD44 gene are HGNC:1681, Entrez Gene:960, Ensembl:ENSG00000026508, OMIM:107269, and UniProtKB:P16070. As used herein, the term “CD44” is not intended to be limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but is intended to include all such forms unless the context specifies the form of the subject to be intended. To avoid misunderstanding, a CD44 sequence means any polynucleotide sequence containing a coding sequence or any exon, but also any polypeptide sequence or any part thereof, such as the NCBI reference sequence NM_000610.4 or any allele variant thereof.

[0072] SLC3A2 SLC3A2, or solute carrier family 3 member 2, is known by several different names, including lymphocyte-activating antigen 4F2 large subunit, solute carrier family 3 (activators of dibasic and neutral amino acid transport), member 2, antigen identified by monoclonal antibody 4F2, TRA1.10, TROP4, and T43, solute carrier family 3 (amino acid transporter heavy chain), member 2, 4F2 cell surface antigen heavy chain, CD98 heavy chain, 4F2HC, MDU1, monoclonal antibody 4F2, antigen defined by heavy chain, antigen defined by monoclonal antibody 4F2, 4F2 heavy chain antigen, CD98 antigen, CD98HC, 4T2HC, NACAE, CD98, and 4F2. The external IDs for SLC3A2 are HGNC:11026, Entrez Gene:6520, Ensembl:ENSG00000168003, OMIM:158070, and UniProtKB:P08195. As used herein, the term “SLC3A2” is not intended to be limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but is intended to include all such forms unless the context specifies the form of the subject to be intended. To avoid misunderstanding, the SLC3A2 transcription version 6 sequence means any polynucleotide sequence containing any coding sequence or any exon, but also means any polypeptide sequence or any part thereof, such as the NCBI reference sequence NM_001013251.3 or any allele variant thereof. Furthermore, the SCL3A2 transcription version 3 sequence refers to any polynucleotide sequence containing a coding sequence or any exon, but also to any polypeptide sequence or any portion thereof, such as the NCBI reference sequence NM_002394.6 or any allele variant thereof.

[0073] VTCN1 VTCN1 is known by several different names, including the V-Set domain containing T cell activation inhibitor 1, B7-H4, B7H4, immune costimulatory protein B7-H4, B7 superfamily member 1, B7 family member, H4, B7 homolog 4, B7h.5, B7S1, T cell costimulatory molecule B7x, protein B7S1, FLJ22418, PRO1291, VCTN1, VTCN1, and B7X. The external IDs for VTCN1 are HGNC:28873, NCBI Entrez Gene:79679, Ensembl:ENSG00000134258, OMIM(registered trademark):608162, and UniProtKB / Swiss-Prot:Q7Z7D3. As used herein, the term “VTCN1” is not intended to be limited to any form such as a protein, RNA, mRNA, cDNA, or DNA sequence, but is intended to include all such forms unless the context specifies the form of the intended subject. To avoid misunderstanding, VTCN1 sequence means any polynucleotide sequence containing a coding sequence or any exon, but also means any polypeptide sequence or any part thereof, such as the NCBI reference sequence NM_024626.4 or any allele variant thereof.

[0074] CDH1 CDH1, or cadherin 1, is known by several different names, including uvomorrin, cadherin 1, type 1, E-cadherin (epithelial), epithelial cadherin, E-cadherin, cadherin-1, CAM120 / 80, CD324, CDHE, UVO, calcium-dependent adhesion protein, epithelium, epididymal secretory sperm-binding protein, cadherin 1, E-cadherin (epithelial), cell-CAM120 / 80, CD324 antigen, E-cadherin, Arc-1, BCDS1, ECAD, and LCAM. The external IDs for CDH1 are HGNC:1748, NCBI Entrez Gene:999, Ensembl:ENSG00000039068, OMIM(registered trademark):192090, and UniProtKB / Swiss-Prot:P12830. As used herein, the term “CDH1” is not intended to be limited to any form such as a protein, RNA, mRNA, cDNA, or DNA sequence, but is intended to include all such forms unless the context specifies the form of the intended subject. To avoid misunderstanding, a CDH1 sequence means any polynucleotide sequence containing a coding sequence or any exon, but also any polypeptide sequence or any part thereof, such as the NCBI reference sequence NM_001317185.2 or any allele variant thereof.

[0075] CXADR CXADR, or coxsackievirus and adenovirus receptor, is a type I membrane receptor for group B coxsackieviruses and subgroup C adenoviruses. Several transcriptional variants encoding different isoforms have been found for this gene. Diseases associated with CXADR include myocarditis and keratoconjunctivitis. Among its associated pathways are adhesion and allograft rejection. It is a component of the epithelial apical junction complex, which can function as an alloaffinity cell adhesion molecule and is essential for the integrity of the tight junction. It is also involved in the transepithelial migration of leukocytes via adhesion interactions with JAML, a transmembrane protein of the plasma membrane of leukocytes. Interactions between both receptors also mediate the activation of gamma-delta T cells, a subpopulation of T cells present in epithelium and involved in tissue homeostasis and repair. Upon epithelial CXADR binding, JAML induces downstream cell signaling events in gamma-delta T cells via PI3-kinase and MAP-kinase. This results in the proliferation and production of cytokines and growth factors by T cells, which then stimulate epithelial tissue repair. External IDs for CXADRs include HGNC:2559 NCBI Entrez Gene:1525 Ensembl:ENSG00000154639 OMIM(registered trademark):602621 UniProtKB / Swiss-Prot:P78310. As used herein, the term “CXADR” is not intended to be limited to any form such as a protein, RNA, mRNA, cDNA, or DNA sequence, but is intended to include all such forms unless the context specifies the form of the subject. To avoid misunderstanding, CXADR sequence means any polynucleotide sequence containing a coding sequence or any exon, but also means any polypeptide sequence or any part thereof, such as the NCBI reference sequence NM_001207063.2 or any allele variant thereof.

[0076] GTF2E2 GTF2E2, or general transcription factor IIE (TFIIE), is part of the RNA polymerase II transcription initiation complex, recruiting TFIIH and essential for promoter clearance by RNA polymerase II. TFIIE is a heterodimer (and sometimes heterotetramer) of alpha and beta subunits. The protein encoded by this gene represents the beta subunit of TFIIE. Diseases associated with GTF2E2 include trichorrhizosis, non-photosensitive trichorrhizosis, and other related pathways. Among its associated pathways are the apoptotic pathway in synovial fibroblasts and the CCR5 pathway in macrophages. External IDs for GTF2E2 include HGNC:4651, NCBI Entrez Gene:2961, Ensembl:ENSG00000197265, OMIM(registered trademark):189964, and UniProtKB / Swiss-Prot:P29084. As used herein, the term "GTF2E2" is not intended to be limited to any form such as a protein, RNA, mRNA, cDNA, or DNA sequence, but is intended to include all such forms unless the context specifies otherwise. To avoid misunderstanding, a GTF2E2 sequence means any polynucleotide sequence containing a coding sequence or any exon, but also any polypeptide sequence or any part thereof, such as the NCBI reference sequence NM_002095.6 or any allele variant thereof.

[0077] CSMD1 CSMD1 (or CUB and Sushi Multiple Domain 1) is a protein associated with diseases including autism and schizophrenia. External IDs for CSMD1 include HGNC:14026, NCBI Entrez Gene:64478, Ensembl:ENSG00000183117, OMIM®:608397, and UniProtKB / Swiss-Prot:Q96PZ7. As used herein, the term “CSMD1” is not intended to be limited to any form such as a protein, RNA, mRNA, cDNA, or DNA sequence, but is intended to include all such forms unless the context specifies otherwise. To avoid misunderstanding, CSMD1 sequence means any polynucleotide sequence containing a coding sequence or any exon, but also any polypeptide sequence or any part thereof, such as the NCBI reference sequence NM_033225.6 or any allele variant thereof.

[0078] PTN Pleiotrophin, or PTN, is a secreted heparin-binding growth factor as a protein. This protein plays a crucial role in cell proliferation and survival, cell migration, angiogenesis, and tumorigenesis. PTN (pleiotrophin) is a protein-coding gene. Diseases associated with PTN include Peyronie's disease and nasal olfactory neuroblastoma. Among its associated pathways are the GPCR pathway and the apoptotic pathway in synovial fibroblasts. External IDs for PTN include HGNC:9630, NCBI Entrez Gene:5764, Ensembl:ENSG00000105894, OMIM(registered trademark):162095, and UniProtKB / Swiss-Prot:P21246. As used herein, the term "PTN" is not intended to be limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but is intended to include all such forms unless the context specifies the form of the subject to be referred to. To avoid misunderstanding, a PTN sequence means any polynucleotide sequence containing a coding sequence or any exon, but also any polypeptide sequence or any part thereof, such as the NCBI reference sequence NM_001321386.2 or any allele variant thereof.

[0079] ST14 ST14, or ST14 transmembrane serine protease matryptase, is an epithelial-derived, integrated membrane serine protease. This protease is known to form a complex with the Kunitz-type serine protease inhibitor, HAI-1, and to be activated by sphingosine 1-phosphate. This protease has been shown to cleave and activate hepatocyte growth factor / scattering factor and urokinase plasminogen activator, suggesting its function as an epithelial membrane activator for other proteases and potential growth factors. Diseases associated with ST14 include various types of ichthyosis. Among the associated pathways are developmental biology and adhesion. External IDs for ST14 include HGNC:11344, NCBI Entrez Gene:6768, Ensembl:ENSG00000149418, OMIM(registered trademark):606797, and UniProtKB / Swiss-Prot:Q9Y5Y6. As used herein, the term “ST14” is not intended to be limited to any form such as a protein, RNA, mRNA, cDNA, or DNA sequence, but is intended to include all such forms unless the context specifies otherwise. To avoid misunderstanding, an ST14 sequence means any polynucleotide sequence containing a coding sequence or any exon, but also any polypeptide sequence or any part thereof, such as the NCBI reference sequence NM_021978.4 or any allele variant thereof.

[0080] THBS1 THBS1, or thrombospondin 1, is a subunit of a disulfide-linked homotrimeric protein. This protein is an adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions. It can bind to fibrinogen, fibronectin, laminin, type V collagen, and integrin alpha-V / beta-1. This protein has been shown to be involved in platelet aggregation, angiogenesis, and tumorigenesis. Diseases associated with THBS1 include thrombotic thrombocytopenic purpura and Peters-Plus syndrome. Among its associated pathways is the degradation of proteoglycans and extracellular matrix in cancer. Gene ontology (GO) annotations associated with this gene include calcium ion binding and heparin binding. External IDs for THBS1 include HGNC:11785 NCBI Entrez Gene:7057 Ensembl:ENSG00000137801 OMIM(registered trademark):188060 UniProtKB / Swiss-Prot:P07996. As used herein, the term “THBS1” is not limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context specifies a particular form. To avoid misunderstanding, THBS1 sequence means any polynucleotide sequence containing a coding sequence or any exon, but also means any polypeptide sequence or any part thereof, such as the NCBI reference sequence NM_003246.4 or any allele variant thereof.

[0081] AGRN AGRN, or Agrin, is one of several proteins crucial for the development of the neuromuscular junction. The encoded protein contains several laminin Gs, Kazal-type serine protease inhibitors, and epidermal growth factor domains. Further post-translational modifications result in the addition of glycosaminoglycans and disulfide bonds. Mutations in this gene have been observed in one family of congenital myasthenic syndromes affecting the limb girdle muscles. Diseases associated with AGRN include myasthenic syndrome, congenital myasthenic syndrome, and presynaptic congenital myasthenic syndrome. Among its associated pathways are agrin interactions at the neuromuscular junction and blood-brain barrier, as well as the migration of immune cells. External IDs for AGRN include HGNC:329, NCBI Entrez Gene:375790, Ensembl:ENSG00000188157, OMIM(registered trademark):103320, and UniProtKB / Swiss-Prot:O00468. As used herein, the term "AGRN" is not limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but rather includes all such forms unless the context specifies a particular form. To avoid misunderstanding, an AGRN sequence means any polynucleotide sequence containing a coding sequence or any exon, but also any polypeptide sequence or any portion thereof, such as from the NCBI reference sequence NM_001305275.2 or any allele variant thereof.

[0082] PVALB PVALB, or parvalbumin, is a high-affinity calcium ion-binding protein structurally and functionally similar to calmodulin and troponin C. This encoded protein is thought to be involved in muscle relaxation. Diseases associated with PVALB include fish allergy and fetal alcohol syndrome. Gene ontology annotations related to this gene include calcium ion binding and protein heterodimerization activity. External IDs for PVALB include HGNC:9704 NCBI Entrez Gene:5816 Ensembl:ENSG00000100362 OMIM(registered trademark):168890 UniProtKB / Swiss-Prot:P20472. As used herein, the term “PVALB” is not limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context specifies a particular form. To avoid misunderstanding, the PVALB sequence means any polynucleotide sequence containing a coding sequence or any exon, but also any polypeptide sequence or any part thereof, such as the NCBI reference sequence NM_002854.3 or any allele variant thereof.

[0083] APP APP is known by several different names, including amyloid-beta precursor protein, alpha-SAPP, AD1, Alzheimer's disease amyloid A4 protein homolog, amyloid-beta (A4) precursor protein, Alzheimer's disease amyloid protein, cerebral vascular amyloid peptide, amyloid-beta precursor protein, amyloid precursor protein, peptidasenexin-II, proteazenexin-II, PN-II, PreA4, ABPP, APPI, CVAP, beta-amyloid precursor protein, testicular tissue protein Li2, beta-amyloid peptide (1-40), beta-amyloid peptide (1-42), amyloid-beta A4 protein, beta-amyloid peptide, Alzheimer's disease, CTF gamma, ABETA, AAA, PN2, and A4. The external IDs for the APP gene are HGNC:620, Entrez Gene:351, Ensembl:ENSG00000142192, OMIM®:104760, and UniProtKB / Swiss-Prot:P05067. As used herein, the term “APP” is not limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context specifies a particular form. To avoid misunderstanding, APP sequence means any polynucleotide sequence containing a coding sequence or any exon, but also any polypeptide sequence or any part thereof, such as from the NCBI reference sequence NM_001136130.3, or any allele variant thereof.

[0084] WRN WRN, or Werner syndrome ATP-dependent helicase, is known by several different names, including WRN RecQ-like helicase, RECQL2, RECQ3, Werner syndrome RecQ-like helicase, DNA helicase, RecQ-like type 3, RecQ protein-like 2, exonuclease WRN, Werner syndrome, RecQ helicase-like, Werner syndrome, EC3.6.4.12, RECQL3, and RecQ3. The external IDs for the WRN gene are HGNC:12791, NCBI Entrez Gene:7486, Ensembl:ENSG00000165392, OMIM®:604611, and UniProtKB / Swiss-Prot:Q14191. As used herein, the term "WRN" is not limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context specifies a particular form. To avoid misunderstanding, a WRN sequence means any polynucleotide sequence containing a coding sequence or any exon, but also any polypeptide sequence or any part thereof, such as the NCBI reference sequence NM_000553.6 or any allele variant thereof.

[0085] DAAM1 DAAM1, or Dishevelled-associated activator 1 of morphogenesis, is known by several different names, including KIAA0666 and Dishevelled-associated activator 1 of morphogenesis. The external IDs for the DAAM1 gene are HGNC:18142, NCBI Entrez Gene:23002, Ensembl:ENSG00000100592, OMIM®:606626, and UniProtKB / Swiss-Prot:Q9Y4D1. As used herein, the term “DAAM1” is not limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context specifies a particular form. To avoid misunderstanding, DAAM1 sequence means any polynucleotide sequence containing a coding sequence or any exon, but also any polypeptide sequence or any part thereof, such as the NCBI reference sequence NM_001270520.2 or any allele variant thereof.

[0086] ASPH ASPH, or aspartate beta-hydroxylase, is known by several different names, including BAH, CASQ2BP1, JCTN, HAAH, aspartyl / asparaginyl beta-hydroxylase, peptide-aspartate beta-dioxygenase, ASP beta-hydroxylase, junctate, junctin, humbug, cardiac junctin, EC1.14.11.16, A beta HJJ, FDLAB, and AAH. The external IDs for the ASPH gene are HGNC:757, Entrez Gene:444, Ensembl:ENSG00000198363, OMIM(registered trademark):600582, and UniProtKB / Swiss-Prot:Q12797. As used herein, the term "ASPH" is not limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but rather includes all such forms unless the context specifies a particular form. To avoid misunderstanding, an ASPH sequence means any polynucleotide sequence containing a coding sequence or any exon, but also means any polypeptide sequence or any part thereof, such as the NCBI reference sequence NM_001164750.2 or any allele variant thereof.

[0087] NOTCH2 NOTCH2, or Notch receptor 2, is known by several different names, including Notch2, Neurogenic Locus Notch Homolog Protein 2, HN2, Notch (Drosophila) Homolog 2, Notch Homolog 2 (Drosophila), Notch Homolog 2, HJCYS, and AGS2. The external IDs for the NOTCH2 gene are HGNC:7882, NCBI Entrez Gene:4853, Ensembl:ENSG00000134250, OMIM®:600275, and UniProtKB / Swiss-Prot:Q04721. As used herein, the term “NOTCH2” is not limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context specifies the intended form. To avoid misunderstanding, the NOTCH2 sequence refers to any polynucleotide sequence containing a coding sequence or any exon, but also to any polypeptide sequence or any part thereof, such as the NCBI reference sequence NM_024408.4 or any allele variant thereof.

[0088] CD74 CD74 is known by several different names, including CD74 molecule, DHLAG, CD74 molecule, major histocompatibility complex, class II invariant chain, HLA class II histocompatibility antigen gamma chain, class II MHC-associated invariant chain peptide, HLA-DR antigen-associated invariant chain, gamma chain of class II antigen, Ia-associated invariant chain, MHC HLA-DR gamma chain, HLA-DR-gamma, CLIP, Ia antigen-associated invariant chain, CD74 antigen, Ia-gamma, HLADG, P33, II, and Ii. The external IDs for the CD74 gene are HGNC:1697, NCBI Entrez Gene:972, Ensembl:ENSG00000019582, OMIM(registered trademark):142790, and UniProtKB / Swiss-Prot:P04233. As used herein, the term “CD74” is not limited to any form such as a protein, RNA, mRNA, cDNA, or DNA sequence, but rather includes all such forms unless the context specifies a particular form. To avoid misunderstanding, a CD74 sequence means any polynucleotide sequence containing a coding sequence or any exon, but also any polypeptide sequence or any part thereof, such as the NCBI reference sequence NM_001025159.3 or any allele variant thereof.

[0089] SDC4 SDC4, or syndecan 4, is known by several different names, including amphiglycan, SYND4, syndecan 4 (amphiglycan, lyudocan), syndecan proteoglycan 4, lyudocan core protein, syndecan-4, lyudocan, and lyudocan amphiglycan. The external IDs for the SDC4 gene are HGNC:10661, NCBI Entrez Gene:6385, Ensembl:ENSG00000124145, OMIM®:600017, and UniProtKB / Swiss-Prot:P31431. As used herein, the term “SDC4” is not limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context specifies the intended form. To avoid misunderstanding, the term SDC4 sequence means any polynucleotide sequence containing a coding sequence or any exon, but also any polypeptide sequence or any part thereof, such as the NCBI reference sequence NM_002999.4 or any allele variant thereof.

[0090] SLC4A4 SLC4A4, or solute carrier family 4 member 4, is known by several different names, including NBC1, HNBC1, HhNMC, NBC2, PNBC, solute carrier family 4 (sodium bicarbonate cotransporter), member 4, electro-generating sodium bicarbonate cotransporter 1, Na(+) / HCO3(-) cotransporter, SLC4A5, KNBC1, sodium bicarbonate cotransporter 1 (sodium bicarbonate cotransporter, kidney, sodium bicarbonate cotransporter, pancreas), solute carrier family 4, sodium bicarbonate cotransporter, member 4, brain type, solute carrier family 4, sodium bicarbonate cotransporter, member 4, solute carrier family 4, sodium bicarbonate cotransporter, member 4, solute carrier family 4, sodium bicarbonate cotransporter, member 5, sodium bicarbonate cotransporter, NBCe1-A, NBCE1, KNBC, and NBC. The external IDs for the SLC4A4 gene are HGNC:11030, NCBI Entrez Gene:8671, Ensembl:ENSG00000080493, OMIM®:603345, and UniProtKB / Swiss-Prot:Q9Y6R1. As used herein, the term “SLC4A4” is not limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context specifies a particular form. To avoid misunderstanding, the SLC4A4 sequence means any polynucleotide sequence containing a coding sequence or any exon, but also means any polypeptide sequence or any part thereof, such as the NCBI reference sequence NM_001098484.3 or any allele variant thereof.

[0091] ZFAT ZFAT, or zinc finger and AT-hook domain-containing proteins, are known by several different names, including zinc finger protein 406, KIAA1485, ZNF406, ZFAT1, zinc finger protein ZFAT, zinc finger gene in autoimmune thyroid disease, zinc finger gene in AITD-sensitive region, and AITD3. The external IDs for the ZFAT gene are HGNC:19899, ​​NCBI Entrez Gene:57623, Ensembl:ENSG00000066827, OMIM®:610931, and UniProtKB / Swiss-Prot:Q9P243. As used herein, the term "ZFAT" is not limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context specifies a particular form. To avoid misunderstanding, a ZFAT sequence means any polynucleotide sequence containing a coding sequence or any exon, but also any polypeptide sequence or any part thereof, such as the NCBI reference sequence NM_020863.4 or any allele variant thereof.

[0092] DSCAML1 DSCAML1, or DS cell adhesion molecule-like 1, is known by several different names, including KIAA1132, Down syndrome cell adhesion molecule-like protein 1, Down syndrome cell adhesion molecule 2, DSCAM2, Down syndrome cell adhesion molecule-like 1, Down syndrome cell adhesion molecule-like 1, and DSCAM-like 1. The external IDs for the DSCAML1 gene are HGNC:14656, NCBI Entrez Gene:57453, Ensembl:ENSG00000177103, OMIM®:611782, and UniProtKB / Swiss-Prot:Q8TD84. As used herein, the term “DSCAML1” is not limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context specifies a particular form. To avoid misunderstanding, the DSCAML1 sequence refers to any polynucleotide sequence containing a coding sequence or any exon, but also to any polypeptide sequence or any part thereof, such as the NCBI reference sequence NM_020693.4 or any allele variant thereof.

[0093] NRG1 polynucleotide fusion This disclosure provides previously unknown gene rearrangements that result in the expression of an NRG1 fusion product in which NRG1 is fused with a fusion partner. In particular, polynucleotide fusions containing NRG1 are provided, including VAPB-NRG1, CADM1-NRG1, CD44-NRG1, SLC3A2-NRG1, VTCN1-NRG1, CDH1-NRG1, CXADR-NRG1, GTF2E2-NRG1, CSMD1-NRG1, PTN-NRG1, ST14-NRG1, THBS1-NRG1, AGRN-NRG1, PVALB-NRG1, APP-NRG1, WRN-NRG1, DAAM1-NRG1, ASPH-NRG1, NOTCH2-NRG1, CD74-NRG1, SDC4-NRG1, SLC4A4-NRG1, ZFAT-NRG1, or DSCAML1-NRG1. Specifically, such fusions are present in or have been identified in human patients diagnosed with cancer, and will be discussed in more detail in the following sections.

[0094] In certain embodiments, the NRG1 fusion may include an additional downstream fusion partner 3' of a nucleic acid sequence encoding an EGF-like domain.

[0095] VAPB-NRG1 polynucleotide fusion The present disclosure provides a polynucleotide comprising a VAPB nucleic acid sequence (or a portion of a VAPB nucleic acid sequence) fused with an NRG1 nucleic acid sequence (or a portion of an NRG1 nucleic acid sequence). The fusion also includes allelic variants of the VAPB and NRG1 nucleic acid sequences.

[0096] Preferably, the VAPB nucleic acid sequence or a portion thereof contains or consists of any one of SEQ ID NOs: 17-23 or any allele variant of any one of SEQ ID NOs: 17-23, and the NRG1 nucleic acid sequence or a portion thereof contains or consists of any one of SEQ ID NOs: 125-138 or any allele variant of any one of SEQ ID NOs: 125-138. More preferably, the VAPB nucleic acid sequence contains a portion of SEQ ID NO: 23 or an allele variant of SEQ ID NO: 23, and the NRG1 nucleic acid sequence preferably contains a portion of SEQ ID NO: 138 or an allele variant of SEQ ID NO: 138. SEQ ID NOs: 17-22 each correspond to individual exons 1-6 of VAPB according to NM_004738.4. SEQ ID NO: 23 corresponds to exons 1-6 of VAPB according to NM_004738.4. SEQ ID NOs: 125-137 each correspond to individual exons 1-13 of the NRG1 sequence according to NM_001159999. Sequence ID 138 corresponds to exons 1-13 of NRG1 following NM_001159999.

[0097] In a preferred embodiment, a portion of the VAPB nucleic acid sequence comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids derived from any one of SEQ ID NOs: 17-23 or any allele variant of any one of SEQ ID NOs: 17-23, and a portion of the NRG1 nucleic acid sequence comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids derived from any one of SEQ ID NOs: 125-138 or any allele variant of any one of SEQ ID NOs: 125-138.

[0098] Preferably, the VAPB nucleic acid sequence or a portion thereof is 5' relative to the NRG1 nucleic acid sequence or a portion thereof.

[0099] Preferably, a polynucleotide containing the VAPB nucleic acid sequence or a portion of the sequence of VAPB fused with the NRG1 nucleic acid sequence or a portion of the sequence contains or encodes the EGF-like domain of NRG1. Abnormal cells containing or expressing a VAPB-NRG1 polynucleotide fusion contain or encode the EGF-like domain of NRG1. For detection, diagnosis, or specific purposes, it may be sufficient to indicate that the fusion junction between VAPB and NRG1 is within a frame and occurs at a position that contains the EGF-like domain of NRG1. The EGF-like domain is preferably an EGF-like domain according to SEQ ID NO: 163, or an allele variant thereof having at least 85% identity to SEQ ID NO: 163, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity thereto.

[0100] Preferably, allele variants of the VAPB nucleic acid sequence have at least 85% identity with any one of sequence numbers 17 to 23, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity with respect to it, and allele variants of the NRG1 nucleic acid sequence have at least 85% identity with any one of sequence numbers 125 to 138, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity with respect to it.

[0101] In a preferred embodiment, the polynucleotide containing the VAPB nucleic acid fused with the NRG1 nucleic acid contains 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 3, preferably the nucleic acids at positions 43 and 44. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids from SEQ ID NO: 3, preferably containing nucleic acids at positions 43 and 44.

[0102] In preferred embodiments, a polynucleotide is provided that includes a polynucleotide according to SEQ ID NO: 3, or a polynucleotide comprising about 20, about 30, about 40, or all consecutive nucleic acids from SEQ ID NO: 3, preferably comprising nucleic acids at positions 43 and 44. The number of consecutive nucleic acids may be 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all nucleic acids from SEQ ID NO: 3, preferably comprising nucleic acids at least at positions 43 and 44.

[0103] Preferably, the polynucleotide portion of the NRG1 nucleic acid sequence (or its allele variant) encodes the EGF-like domain of NRG1, preferably the EGF-like domain according to Sequence ID No. 163.

[0104] In an alternative embodiment, a polynucleotide is provided comprising a portion of exon 1 of VAPB, or an allele variant thereof, fused with a portion of exon 2 of NRG1, or an allele variant thereof. Preferably, exon 1 of VAPB is the exon of SEQ ID NO: 17. Preferably, exon 2 of NRG1 is the exon of SEQ ID NO: 126. The portion of exon 1 of VAPB preferably comprises or consists of SEQ ID NO: 1 or an allele variant thereof. The portion of exon 2 of NRG1 preferably comprises or consists of SEQ ID NO: 2 or an allele variant thereof. When present in abnormal cells of a patient or subject, the polynucleotide fusion preferably further comprises any sequence 3' from exon 2 of NRG1, and the presence of at least SEQ ID NOs: 17 and 126 may be sufficient to enable detection of the fusion junction using a polynucleotide-based detection assay. Any sequence 3' from exon 2 of NRG1 contains or consists of one or all of sequence numbers 127-137 (or any allele variant of sequence numbers 127-137).

[0105] Preferably, the allele variant of exon 1 of VAPB has at least 85% identity with SEQ ID NO: 17, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity, and the allele variant of exon 2 of NRG1 has at least 85% identity with SEQ ID NO: 126, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0106] In a preferred embodiment, a portion of exon 1 of VAPB contains or comprises SEQ ID NO: 1, and its allele variants have at least 85% identity with respect to SEQ ID NO: 1, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. A portion of exon 2 of NRG1 in this fusion preferably contains or comprises SEQ ID NO: 2, and its allele variants have at least 85% identity with respect to SEQ ID NO: 2, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. Such short polynucleotide sequences are particularly useful for detecting the presence of a larger polynucleotide fusion between VAPB and NRG1, and for establishing that such a fusion is an intraframe oncogenic fusion containing the EGF-like domain of NRG1. More preferably, a portion of exon 1 of VAPB contains or consists of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 1, and contains at least 43 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all nucleic acids from SEQ ID NO: 1, and contains at least 43 nucleic acids. More preferably, a portion of exon 1 of VAPB includes or follows SEQ ID NO: 1 or its allele variant.

[0107] Alternatively, a portion of exon 1 of VAPB contains or comprises SEQ ID NO: 17 (or an allele variant of SEQ ID NO: 17) and comprises at least 399 nucleic acids. Preferably, a portion of exon 1 of VAPB contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 17 or its allele variants, and comprises at least 399 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids in SEQ ID NO: 17, and may include at least 399 nucleic acids. In this alternative example, a portion of exon 1 of VAPB more preferably includes or follows SEQ ID NO: 17 or its allele variant. Preferably, the portion of exon 2 of NRG1 in the fusion with VAPB contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 126 or its allele variants, and contains at least the nucleic acid at position 1. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 of the nucleic acids in SEQ ID NO: 126, and may include at least the nucleic acid at position 1.

[0108] In alternatively preferred embodiments, the polynucleotide comprising a portion of exon 1 of VAPB fused with a portion of exon 2 of NRG1 comprises 2 to about 10, about 20, about 30, or up to about 40, or all consecutive nucleic acids from SEQ ID NO: 3, including nucleic acids at positions 43 and 44. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids, and may include nucleic acids at least at positions 43 and 44. Sequence ID 3 includes a junction between VAPB and NRG1, and in particular, the junction is between the nucleic acid at position 43 derived from VAPB and the nucleic acid at position 44 derived from NRG1. Preferably, the polynucleotide containing a portion of exon 1 of VAPB fused with a portion of exon 2 of NRG1 has the polynucleotide sequence of SEQ ID NO: 3, or an allele variant thereof.

[0109] Preferably, any VAPB-NRG1 polynucleotide fusion provided herein is an intraframe fusion of VAPB and NRG1. More preferably, the fusion is an intraframe fusion comprising exon 1 or a portion of exon 1 of VAPB and exon 2 or a portion of exon 2 of NRG1. The intraframe fusion is preferably the fusion of SEQ ID NO: 3 or an allele variant thereof.

[0110] Preferably, exon 1 of VAPB or a portion of its allele variant is 5' relative to exon 2 of NRG1 or a portion of its allele variant. This orientation at the nucleic acid level results in a fusion polypeptide product containing the N-terminus of VAPB and the C-terminus of NRG1. The VAPB-NRG1 polynucleotide fusion provided herein also produces a protein fusion, where the portion from the N-terminus to the fusion junction is a polypeptide sequence from VAPB, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, with the NRG1 portion also providing its EGF-like domain. Thus, the VAPB-NRG1 fusion protein retains the EGF-like domain of NRG1 and retains the ability to promote the growth and survival of a subset of human cancers, including lung cancer or adenocarcinoma, particularly lung adenocarcinoma or non-small cell lung cancer.

[0111] CADM1-NRG1 polynucleotide fusion A polynucleotide fusion is also provided, comprising a portion of exon 7 of CADM1 fused with a portion of exon 6 of NRG1. The exon 7 of CADM1 is preferably the exon of SEQ ID NO: 39 or the allele variant of SEQ ID NO: 39, and the exon 6 of NRG1 is preferably the exon of SEQ ID NO: 130 or the allele variant of SEQ ID NO: 130.

[0112] Preferably, the allele variant of exon 7 of CADM1 has at least 85% identity with SEQ ID NO: 39, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity, and the allele variant of exon 6 of NRG1 has at least 85% identity with SEQ ID NO: 130, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0113] Preferably, a portion of exon 7 of CADM1 contains or conforms to SEQ ID NO: 5, and its allele variants have at least 85% identity to SEQ ID NO: 5, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. A portion of exon 6 of NRG1 in the fusion with CADM1 is preferably a sequence conforming to or containing SEQ ID NO: 6, and its allele variants have at least 85% identity to SEQ ID NO: 6, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. Such short polynucleotide sequences are particularly useful for detecting the presence of a larger polynucleotide fusion between CADM1 and NRG1, and for establishing that such a fusion is an intraframe oncogenic fusion containing the EGF-like domain of NRG1. More preferably, a portion of exon 7 of CADM1 contains or consists of 2 to about 10, about 20, about 30, or up to about 40, or even all of the consecutive nucleic acids from SEQ ID NO: 5, and contains at least 53 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids from SEQ ID NO: 5, and contains at least 53 nucleic acids. More preferably, a portion of exon 7 of CADM1 comprises or follows SEQ ID NO: 5, or its allele variant.

[0114] Alternatively, a portion of exon 7 of CADM1 contains or comprises SEQ ID NO: 39 (or an allele variant of SEQ ID NO: 39) and comprises at least 173 nucleic acids. Preferably, a portion of exon 7 of CADM1 contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 39 or its allele variants, and comprises at least 173 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids, and may include at least 173 nucleic acids. In this alternative example, a portion of exon 7 of CADM1 more preferably includes or follows sequence number 39 or its allele variant. Preferably, the portion of exon 6 of NRG1 in the fusion with CADM1 contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 130 or its allele variants, and contains at least one nucleic acid. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 of the nucleic acids in SEQ ID NO: 130, and may include at least the nucleic acid at position 1.

[0115] In alternatively preferred embodiments, the polynucleotide comprising a portion of exon 7 of CADM1 fused with a portion of exon 6 of NRG1 comprises 2 to about 10, about 20, about 30, or up to about 40, or all consecutive nucleic acids from SEQ ID NO: 7, including the nucleic acids at positions 53 and 54. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids, and may include nucleic acids at least at positions 53 and 54. Sequence ID 7 includes a junction between CADM1 and NRG1, and in particular, the junction is between the nucleic acid at position 53 derived from CADM1 and the nucleic acid at position 54 derived from NRG1. Preferably, the polynucleotide containing a portion of exon 7 of CADM1 fused with a portion of exon 6 of NRG1 has the polynucleotide sequence of SEQ ID NO: 7, or an allele variant thereof.

[0116] In preferred embodiments, a polynucleotide is provided that includes a polynucleotide according to SEQ ID NO: 7, or a polynucleotide comprising about 20, about 30, about 40, or all consecutive nucleic acids from SEQ ID NO: 7, preferably comprising nucleic acids at positions 53 and 54. The number of consecutive nucleic acids may be 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all nucleic acids from SEQ ID NO: 7, preferably comprising nucleic acids at least at positions 53 and 54.

[0117] Preferably, any CADM1-NRG1 polynucleotide fusion provided herein is an intraframe fusion of CADM1 and NRG1. More preferably, the fusion is an intraframe fusion comprising exon 7 or a portion of exon 7 of CADM1 and exon 6 or a portion of exon 6 of NRG1. The intraframe fusion is preferably the fusion of SEQ ID NO: 7, or an allele variant thereof having at least 85% identity thereto, preferably at least 90%, 92%, 94%, 96%, or 98% identity thereto.

[0118] Preferably, a polynucleotide comprising a portion of exon 6 of NRG1, or a portion of exon 7 of CADM1 fused with an allele variant thereof, or an allele variant thereof, further comprises a portion of a longer polynucleotide that comprises or encodes the EGF-like domain of NRG1. Abnormal cells comprising a polynucleotide fusion expressing CADM1 or a polypeptide fusion comprises or encodes the EGF-like domain of NRG1. For rapid detection, diagnosis, or specific purposes, it may be sufficient to indicate that the fusion junction between CADM1 and NRG1 is within a frame and occurs at a position that contains the EGF-like domain of NRG1. The EGF-like domain is preferably an EGF-like domain according to SEQ ID NO: 163, or an allele variant thereof having at least 85% identity to SEQ ID NO: 163, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity thereto.

[0119] Preferably, exon 7 of CADM1 or a portion of its allele variant is 5' relative to exon 6 of NRG1 or a portion of its allele variant. This orientation at the nucleic acid level results in a fusion polypeptide product containing the N-terminus of CADM1 and the C-terminus of NRG1. Furthermore, the CADM1-NRG1 polynucleotide fusion provided herein produces a protein fusion in which the portion from the N-terminus to the fusion junction is a polypeptide sequence from CADM1, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, with the NRG1 portion also providing its EGF-like domain. Thus, the CADM1-NRG1 fusion protein retains the EGF-like domain of NRG1 and retains the ability to promote the growth and survival of a subset of human cancers, including lung cancer or adenocarcinoma, particularly lung adenocarcinoma.

[0120] When present in abnormal cells of a patient or subject, the CADM1-NRG1 polynucleotide fusion preferably further comprises any sequence 5' from exon 7 of CADM1 and any sequence 3' from exon 6 of NRG1, and it may be sufficient to have at least SEQ ID NOs. 39 and 130 to enable detection of the fusion junction using a polynucleotide-based detection assay. The any sequence 5' from exon 7 of CADM1 comprises or consists of one or all of SEQ ID NOs. 33-38 (or any allele variant of SEQ ID NOs. 33-38), and the any sequence 3' from exon 6 of NRG1 comprises or consists of any one or all of SEQ ID NOs. 131-137 (or any allele variant of SEQ ID NOs. 131-137).

[0121] CD44-NRG1 polynucleotide fusion A polynucleotide fusion is also provided, comprising a portion of exon 5 of CD44 fused with a portion of exon 2 of NRG1. The exon 5 of CD44 is preferably the exon of SEQ ID NO: 65 or an allele variant of SEQ ID NO: 65, and the exon 2 of NRG1 is preferably the exon of SEQ ID NO: 126 or an allele variant of SEQ ID NO: 126.

[0122] Preferably, the allele variant of exon 5 of CD44 has at least 85% identity with SEQ ID NO: 65, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity, and the allele variant of exon 2 of NRG1 has at least 85% identity with SEQ ID NO: 126, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0123] Preferably, a portion of exon 5 of CD44 contains or follows sequence number 9, and its allele variants have at least 85% identity with respect to sequence number 9, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. A portion of exon 2 of NRG1 in the fusion with CD44 is preferably a sequence following or including sequence number 10, and its allele variants have at least 85% identity with respect to sequence number 10, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, a portion of exon 5 of CD44 contains or consists of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from sequence number 9, and includes at least 52 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids, and may include at least 52 nucleic acids. More preferably, a portion of exon 5 of CD44 includes or follows sequence number 9 or its allele variant. Such short polynucleotide sequences are particularly useful for detecting the presence of larger polynucleotide fusions between CD44 and NRG1, and for establishing that such fusions are intraframe oncogenic fusions containing the EGF-like domain of NRG1.

[0124] Alternatively, a portion of exon 5 of CD44 contains or comprises SEQ ID NO: 65 (or an allele variant of SEQ ID NO: 65) and includes at least 231 nucleic acids. Preferably, a portion of exon 5 of CD44 contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 65 or its allele variants, and includes at least 231 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids, and may include at least 231 nucleic acids. In this alternative example, a portion of exon 5 of CD44 more preferably includes or follows sequence number 231 or its allele variant. Preferably, the portion of exon 2 of NRG1 in the fusion with CD44 contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 126 or its allele variant, and contains at least one nucleic acid. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 of the nucleic acids in SEQ ID NO: 126, and may include at least the nucleic acid at position 1.

[0125] In alternatively preferred embodiments, the polynucleotide comprising a portion of exon 5 of CD44 fused with a portion of exon 2 of NRG1 comprises 2 to about 10, about 20, about 30, or up to about 40, or all consecutive nucleic acids from SEQ ID NO: 11, including the nucleic acids at positions 52 and 53. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids, and may include nucleic acids at least at positions 52 and 53. Sequence ID 11 includes a junction between CD44 and NRG1, and in particular, the junction is between the nucleic acid at position 52 derived from CD44 and the nucleic acid at position 53 derived from NRG1. Preferably, the polynucleotide containing a portion of exon 5 of CD44 fused with a portion of exon 2 of NRG1 has the polynucleotide sequence of SEQ ID NO: 15, or an allele variant thereof.

[0126] In a preferred embodiment, a polynucleotide is provided that includes a polynucleotide according to SEQ ID NO: 11, or a polynucleotide comprising about 20, about 30, about 40, or all consecutive nucleic acids from SEQ ID NO: 11, preferably containing nucleic acids at positions 52 and 53. The number of consecutive nucleic acids may be 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all nucleic acids from SEQ ID NO: 11, preferably containing nucleic acids at least at positions 52 and 53.

[0127] Preferably, any CD44-NRG1 polynucleotide fusion provided herein is an intraframe fusion of CD44 and NRG1. More preferably, the fusion is an intraframe fusion comprising exon 5 (or a portion of exon 5) of CD44 and exon 2 (or a portion of exon 2) of NRG1. The intraframe fusion is preferably the fusion of SEQ ID NO: 11, or an allele variant thereof having at least 85% identity thereto, preferably at least 90%, 92%, 94%, 96%, or 98% identity thereto.

[0128] Preferably, a polynucleotide comprising a portion of exon 2 of NRG1, or a portion of exon 5 of CD44 fused with an allele variant thereof, or an allele variant thereof, further comprises a portion of a longer polynucleotide that comprises or encodes the EGF-like domain of NRG1. Abnormal cells comprising CD44 or polynucleotide fusions expressing a polypeptide fusion contain or encode the EGF-like domain of NRG1. For rapid detection, diagnosis, or specific purposes, it may be sufficient to indicate that the fusion junction between CD44 and NRG1 is within a frame and occurs at a position that contains the EGF-like domain of NRG1. The EGF-like domain is preferably an EGF-like domain according to SEQ ID NO: 163, or an allele variant thereof having at least 85% identity to SEQ ID NO: 163, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity thereto.

[0129] Preferably, exon 5 of CD44 or a portion of its allele variant is 5' relative to exon 2 of NRG1 or a portion of its allele variant. This orientation at the nucleic acid level results in a fusion polypeptide product containing the N-terminus of CD44 and the C-terminus of NRG1. The CD44-NRG1 polynucleotide fusion provided herein also produces a protein fusion, where the portion from the N-terminus to the fusion junction is a polypeptide sequence from CD44, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, with the NRG1 portion also providing its EGF-like domain. Thus, the CD44-NRG1 fusion protein retains the EGF-like domain of NRG1 and retains the ability to promote the growth and survival of a subset of human cancers, including pancreatic cancer or pancreatic adenocarcinoma, particularly pancreatic ductal adenocarcinoma.

[0130] When present in abnormal cells of a patient or subject, the CD44-NRG1 polynucleotide fusion preferably further comprises any sequence 5' from exon 5 of CD44 and any sequence 3' from exon 2 of NRG1, and it may be sufficient to have at least SEQ ID NOs. 65 and 126 present to enable detection of the fusion junction using a polynucleotide-based detection assay. The any sequence 5' from exon 5 of CD44 comprises or consists of one or all of SEQ ID NOs. 61-64 (or any allele variant of SEQ ID NOs. 61-64), and the any sequence 3' from exon 2 of NRG1 comprises or consists of one or all of SEQ ID NOs. 127-137 (or any allele variant of SEQ ID NOs. 127-137).

[0131] Furthermore, a polynucleotide fusion is provided that includes a portion of exon 5 of CD44 fused with a portion of exon 6 of NRG1. The exon 5 of CD44 is preferably the exon of SEQ ID NO: 65 or an allele variant of SEQ ID NO: 65, and the exon 6 of NRG1 is preferably the exon of SEQ ID NO: 130 or an allele variant of SEQ ID NO: 130.

[0132] Preferably, the allele variant of exon 5 of CD44 has at least 85% identity with SEQ ID NO: 65, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity, and the allele variant of exon 6 of NRG1 has at least 85% identity with SEQ ID NO: 130, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0133] Preferably, a portion of exon 5 of CD44 contains or conforms to sequence number 759, and the allele variant has at least 85% identity with respect to sequence number 759, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. A portion of exon 6 of NRG1 in the fusion with CD44 is preferably a sequence conforming to or containing sequence number 760, and the allele variant has at least 85% identity with respect to sequence number 760, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, a portion of exon 5 of CD44 contains or consists of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from sequence number 759, and contains at least the nucleic acid at position 75. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 759, and may include at least 75 nucleic acids. More preferably, a portion of exon 5 of the CD44 includes or follows SEQ ID NO: 759 or its allele variant. Such short polynucleotide sequences are particularly useful for detecting the presence of a larger polynucleotide fusion between CD44 and NRG1, and for establishing that such a fusion is an intraframe oncogenic fusion containing the EGF-like domain of NRG1.

[0134] Alternatively, a portion of exon 5 of CD44 may contain or consist of SEQ ID NO: 65 (or an allele variant of SEQ ID NO: 65) and include at least 231 nucleic acids. Preferably, a portion of exon 5 of CD44 may contain or consist of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 65 or its allele variants, and include at least 231 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids, and may include at least 231 nucleic acids. In this alternative example, a portion of exon 5 of CD44 more preferably includes or follows sequence number 65 or its allele variant. Preferably, a portion of exon 6 of NRG1 in the fusion with CD44 contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 130 or its allele variants, and contains at least one nucleic acid. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 of the nucleic acids in SEQ ID NO: 130, and may include at least the nucleic acid at position 1.

[0135] Preferably, any CD44-NRG1 polynucleotide fusion provided herein is an intraframe fusion of CD44 and NRG1. More preferably, the fusion is an intraframe fusion comprising exon 5 or a portion of exon 5 of CD44 and exon 6 or a portion of exon 6 of NRG1. The intraframe fusion is preferably the fusion of SEQ ID NO: 761, or an allele variant thereof having at least 85% identity thereto, preferably at least 90%, 92%, 94%, 96%, or 98% identity thereto.

[0136] In alternatively preferred embodiments, the polynucleotide comprising a portion of exon 5 of CD44 fused with a portion of exon 6 of NRG1 comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 761, including the nucleic acids at positions 75 and 76. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids in sequence number 761, and may include nucleic acids at least at positions 75 and 76. Sequence number 761 includes a junction between CD44 and NRG1, and in particular, the junction is between the nucleic acid at position 75 derived from CD44 and the nucleic acid at position 76 derived from NRG1. Preferably, the polynucleotide containing a portion of exon 5 of CD44 fused with a portion of exon 6 of NRG1 has the polynucleotide sequence of SEQ ID NO: 761, or an allele variant thereof.

[0137] In preferred embodiments, a polynucleotide is provided that includes a polynucleotide according to SEQ ID NO: 761, or a polynucleotide comprising about 20, about 30, about 40, or all consecutive nucleic acids from SEQ ID NO: 761, preferably comprising nucleic acids at positions 75 and 76. The number of consecutive nucleic acids may be 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all nucleic acids from SEQ ID NO: 761, preferably comprising nucleic acids at least at positions 75 and 76.

[0138] Preferably, a polynucleotide comprising a portion of exon 6 of NRG1, or a portion of exon 5 of CD44 fused with an allele variant thereof, or an allele variant thereof, further comprises a portion of a longer polynucleotide that comprises or encodes the EGF-like domain of NRG1. Abnormal cells comprising the CD44 or a polynucleotide fusion expressing the polypeptide fusion contain or encode the EGF-like domain of NRG1. For rapid detection, diagnosis, or specific purposes, it may be sufficient to indicate that the fusion junction between CD44 and NRG1 is within a frame and occurs at a position that contains the EGF-like domain of NRG1. The EGF-like domain is preferably the EGF-like domain according to SEQ ID NO: 163, or an allele variant thereof having at least 85% identity to SEQ ID NO: 163, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity thereto.

[0139] Preferably, exon 5 of CD44 or a portion of its allele variant is 5' relative to exon 6 of NRG1 or a portion of its allele variant. This orientation at the nucleic acid level results in a fusion polypeptide product containing the N-terminus of CD44 and the C-terminus of NRG1. Furthermore, the CD44-NRG1 polynucleotide fusion provided herein produces a protein fusion in which the portion from the N-terminus to the fusion junction is a polypeptide sequence from CD44, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, with the NRG1 portion also providing its EGF-like domain. Thus, the CD44-NRG1 fusion protein retains the EGF-like domain of NRG1 and retains the ability to promote the growth and survival of human cancers, particularly subsets of pancreatic cancer.

[0140] When present in abnormal cells of a patient or subject, the polynucleotide fusion preferably further comprises any sequence 5' from exon 5 of CD44 and any sequence 3' from exon 6 of NRG1, and it may be sufficient to have at least SEQ ID NOs. 65 and 130 to enable detection of the fusion junction using a polynucleotide-based detection assay. The any sequence 5' from exon 5 of CD44 comprises or consists of one or all of SEQ ID NOs. 61-64 (or any allele variant of SEQ ID NOs. 61-64), and the any sequence 3' from exon 6 of NRG1 comprises or consists of one or all of SEQ ID NOs. 131-137 (or any allele variant of SEQ ID NOs. 131-137).

[0141] SLC3A2-NRG1 polynucleotide fusion A polynucleotide fusion is also provided that includes a portion of exon 1 of SLC3A2 fused with a portion of exon 5 of NRG1. The exon 1 of SLC3A2 is preferably the exon of SEQ ID NO: 103 or an allele variant of SEQ ID NO: 103, and the exon 5 of NRG1 is preferably the exon of SEQ ID NO: 129 or an allele variant of SEQ ID NO: 129.

[0142] Preferably, the allele variant of exon 1 of SLC3A2 has at least 85% identity with SEQ ID NO: 103, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity, and the allele variant of exon 5 of NRG1 has at least 85% identity with SEQ ID NO: 129, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0143] Preferably, a portion of exon 1 of SLC3A2 contains or conforms to SEQ ID NO: 13, and its allele variants have at least 85% identity with respect to SEQ ID NO: 13, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. A portion of exon 5 of NRG1 in the fusion with SLC3A2 is preferably a sequence conforming to or containing SEQ ID NO: 14, and its allele variants have at least 85% identity with respect to SEQ ID NO: 14, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, a portion of exon 1 of SLC3A2 contains or consists of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 13, and contains at least 53 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids, and may include at least 53 nucleic acids. More preferably, a portion of exon 1 of SLC3A2 includes or follows sequence number 13 or its allele variant. Such short polynucleotide sequences are particularly useful for detecting the presence of a larger polynucleotide fusion between SLC3A2 and NRG1, and for establishing that such a fusion is an intraframe oncogenic fusion containing the EGF-like domain of NRG1.

[0144] Alternatively, a portion of exon 1 of SLC3A2 contains or comprises SEQ ID NO: 103 (or an allele variant of SEQ ID NO: 103) and comprises at least 552 nucleic acids. Preferably, a portion of exon 1 of SLC3A2 contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 103 or its allele variants, and comprises at least 552 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 103, and may include at least 552 nucleic acids. In this alternative example, a portion of exon 1 of SLC3A2 more preferably includes or follows SEQ ID NO: 103 or its allele variant. Preferably, the portion of exon 5 of NRG1 in the fusion with SLC3A2 contains, or comprises, 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 157 or its allele variants, and contains at least one nucleic acid. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 of the nucleic acids in SEQ ID NO: 157, and may include at least the nucleic acid at position 1.

[0145] Preferably, any SLC3A2-NRG1 polynucleotide fusion provided herein is an intraframe fusion of SLC3A2 and NRG1. More preferably, the fusion is an intraframe fusion comprising exon 1 or a portion of exon 1 of SLC3A2 transcription version 6 and exon 5 of NRG1 or a portion of exon 5 of NRG1. The intraframe fusion is preferably the fusion of SEQ ID NO: 15, or an allele variant thereof having at least 85% identity thereto, preferably at least 90%, 92%, 94%, 96%, or 98% identity thereto.

[0146] In an alternatively preferred embodiment, the polynucleotide comprising a portion of exon 1 of SLC3A2 fused with a portion of exon 5 of NRG1 comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 15, including the nucleic acids at positions 53 and 54. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids in SEQ ID NO: 15, and may include nucleic acids at positions 53 and 54. SEQ ID NO: 15 includes a junction between SLC3A2 and NRG1, and in particular, the junction is between the nucleic acid at position 53 derived from SLC3A2 and the nucleic acid at position 54 derived from NRG1. Preferably, the polynucleotide containing a portion of exon 1 of SLC3A2 fused with a portion of exon 5 of NRG1 has the polynucleotide sequence of SEQ ID NO: 15, or an allele variant thereof.

[0147] In preferred embodiments, a polynucleotide is provided that includes a polynucleotide according to SEQ ID NO: 15, or a polynucleotide comprising about 20, about 30, about 40, or all consecutive nucleic acids from SEQ ID NO: 15, preferably comprising nucleic acids at positions 53 and 54. The number of consecutive nucleic acids may be 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all nucleic acids from SEQ ID NO: 15, preferably comprising nucleic acids at least at positions 53 and 54.

[0148] Preferably, a polynucleotide comprising a portion of exon 5 of NRG1, or a portion of exon 1 of transcriptional version 6 of SLC3A2 fused with an allele variant thereof, or an allele variant thereof, further comprises a portion of a longer polynucleotide that comprises or encodes the EGF-like domain of NRG1. Abnormal cells comprising a polynucleotide fusion expressing the SLC3A2 or polypeptide fusion contain or encode the EGF-like domain of NRG1. For rapid detection, diagnosis, or specific purposes, it may be sufficient to indicate that the fusion junction between SLC3A2 and NRG1 is within a frame and occurs at a position that contains the EGF-like domain of NRG1. The EGF-like domain is preferably an EGF-like domain according to SEQ ID NO: 163, or an allele variant thereof having at least 85% identity to SEQ ID NO: 163, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity thereto.

[0149] Preferably, exon 1 of transcriptional version 6 of SLC3A2 or a portion of its allele variant is 5' relative to exon 5 of NRG1 or a portion of its allele variant. This orientation at the nucleic acid level results in a fusion polypeptide product containing the N-terminus of SLC3A2 and the C-terminus of NRG1. The SLC3A2-NRG1 polynucleotide fusion provided herein also produces a protein fusion, where the portion from the N-terminus to the fusion junction is a polypeptide sequence from SLC3A2, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, with the NRG1 portion also providing its EGF-like domain. Thus, the SLC3A2-NRG1 fusion protein retains the EGF-like domain of NRG1 and retains the ability to promote the growth and survival of a subset of human cancers, including lung cancer or adenocarcinoma, particularly lung adenocarcinoma.

[0150] When present in abnormal cells of a patient or subject, the SCL3A2-NRG1 polynucleotide fusion preferably further comprises any sequence 3' from exon 5 of NRG1, and it may be sufficient to have at least SEQ ID NOs. 103 and 129 present to enable detection of the fusion junction using a polynucleotide-based detection assay. Any sequence 3' from exon 5 of NRG1 comprises or consists of one or all of SEQ ID NOs. 130-137 (or any allele variant of SEQ ID NOs. 130-137).

[0151] Furthermore, a polynucleotide fusion is provided that includes a portion of exon 2 of transcription version 3 SLC3A2 fused with a portion of exon 6 of NRG1. The exon 2 of SLC3A2 is preferably the exon of SEQ ID NO: 457 or the allele variant of SEQ ID NO: 457, and the exon 6 of NRG1 is preferably the exon of SEQ ID NO: 130 or the allele variant of SEQ ID NO: 130.

[0152] Preferably, the allele variant of exon 2 of SLC3A2 has at least 85% identity with SEQ ID NO: 457, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity, and the allele variant of exon 6 of NRG1 has at least 85% identity with SEQ ID NO: 130, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0153] Preferably, a portion of exon 2 of SLC3A2 contains or conforms to sequence number 452, and the allele variant has at least 85% identity with respect to sequence number 452, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. A portion of exon 6 of NRG1 in the fusion with SLC3A2 is preferably a sequence conforming to or containing sequence number 453, and the allele variant has at least 85% identity with respect to sequence number 453, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, a portion of exon 2 of SLC3A2 contains or consists of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from sequence number 452, and contains at least 93 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 452, and include at least 93 nucleic acids. More preferably, a portion of exon 2 of SLC3A2 includes or follows SEQ ID NO: 452 or its allele variant. Such short polynucleotide sequences are particularly useful for detecting the presence of a larger polynucleotide fusion between SLC3A2 and NRG1, and for establishing that such a fusion is an intraframe oncogenic fusion containing the EGF-like domain of NRG1.

[0154] Alternatively, a portion of exon 2 of SLC3A2 contains or comprises SEQ ID NO: 457 (or an allele variant of SEQ ID NO: 457) and comprises at least 93 nucleic acids. Preferably, a portion of exon 2 of SLC3A2 contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 457 or its allele variants, and comprises at least 93 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 457, and include at least 93 nucleic acids. In this alternative example, a portion of exon 2 of SLC3A2 more preferably includes or follows SEQ ID NO: 457 or its allele variant. Preferably, in the fusion with transcriptional version 3 of SLC3A2, a portion of exon 6 of NRG1 contains or consists of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 130 or its allele variants, and contains at least one nucleic acid. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 of the nucleic acids in SEQ ID NO: 130, and may include at least the nucleic acid at position 1.

[0155] Preferably, any SLC3A2-NRG1 polynucleotide fusion provided herein is an intraframe fusion of SLC3A2 and NRG1. More preferably, the fusion is an intraframe fusion comprising exon 2 or a portion of exon 2 of SLC3A2 transcription version 3 and exon 6 of NRG1 or a portion of exon 6 of NRG1. The intraframe fusion is preferably the fusion of SEQ ID NO: 454, or an allele variant thereof having at least 85% identity thereto, preferably at least 90%, 92%, 94%, 96%, or 98% identity thereto.

[0156] In an alternatively preferred embodiment, the polynucleotide comprising a portion of exon 2 of SLC3A2 fused with a portion of exon 6 of NRG1 comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 454, including the nucleic acids at positions 93 and 94. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids in sequence number 454, and may include nucleic acids at least at positions 93 and 94. Sequence number 454 includes a junction between SLC3A2 and NRG1, and in particular, the junction is between the nucleic acid at position 93 derived from SLC3A2 and the nucleic acid at position 94 derived from NRG1. Preferably, the polynucleotide containing a portion of exon 2 of SLC3A2 fused with a portion of exon 6 of NRG1 has the polynucleotide sequence of SEQ ID NO: 454, or an allele variant thereof.

[0157] In preferred embodiments, a polynucleotide is provided that includes a polynucleotide according to SEQ ID NO: 454, or a polynucleotide comprising about 20, about 30, about 40, or all consecutive nucleic acids from SEQ ID NO: 454, preferably comprising nucleic acids at positions 93 and 94. The number of consecutive nucleic acids may be 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all nucleic acids from SEQ ID NO: 454, preferably comprising nucleic acids at least at positions 93 and 94.

[0158] Preferably, a polynucleotide comprising a portion of exon 6 of NRG1, or a portion of exon 2 of transcriptional version 3 of SLC3A2 fused with an allele variant thereof, or an allele variant thereof, further comprises a portion of a longer polynucleotide that comprises or encodes the EGF-like domain of NRG1. Abnormal cells comprising a polynucleotide fusion expressing the SLC3A2 or polypeptide fusion contain or encode the EGF-like domain of NRG1. For rapid detection, diagnosis, or specific purposes, it may be sufficient to indicate that the fusion junction between SLC3A2 and NRG1 is within a frame and occurs at a position that contains the EGF-like domain of NRG1. The EGF-like domain is preferably an EGF-like domain according to SEQ ID NO: 163, or an allele variant thereof having at least 85% identity to SEQ ID NO: 163, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity thereto.

[0159] Preferably, exon 2 of transcriptional version 3 of SLC3A2 or a portion of its allele variant is 5' relative to exon 6 of NRG1 or a portion of its allele variant. This orientation at the nucleic acid level results in a fusion polypeptide product containing the N-terminus of SLC3A2 and the C-terminus of NRG1. The SLC3A2-NRG1 polynucleotide fusion provided herein also produces a protein fusion, where the portion from the N-terminus to the fusion junction is a polypeptide sequence from SLC3A2, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, with the NRG1 portion also providing its EGF-like domain. Thus, the SLC3A2-NRG1 fusion protein retains the EGF-like domain of NRG1 and retains the ability to promote the growth and survival of a subset of human cancers, including lung cancer or adenocarcinoma, particularly lung adenocarcinoma.

[0160] When present in abnormal cells of a patient or subject, the SCL3A2-NRG1 polynucleotide fusion preferably further comprises any sequence 3' from exon 6 of NRG1, and it may be sufficient to have at least SEQ ID NOs. 457 and 130 to enable detection of the fusion junction using a polynucleotide-based detection assay. Any sequence 3' from exon 6 of NRG1 comprises or consists of one or all of SEQ ID NOs. 131-137 (or any allele variant of SEQ ID NOs. 131-137).

[0161] VTCN1-NRG1 polynucleotide fusion A polynucleotide fusion is also provided, comprising a portion of exon 2 of VTCN1 fused with a portion of exon 2 of NRG1. The exon 2 of VTCN1 is preferably the exon of SEQ ID NO: 169 or an allele variant of SEQ ID NO: 169, and the exon 2 of NRG1 is preferably the exon of SEQ ID NO: 126 or an allele variant of SEQ ID NO: 126.

[0162] Preferably, the allele variant of exon 2 of VTCN1 has at least 85% identity with SEQ ID NO: 169, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity, and the allele variant of exon 2 of NRG1 has at least 85% identity with SEQ ID NO: 126, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0163] Preferably, a portion of exon 2 of VTCN1 contains or conforms to SEQ ID NO: 164, and its allele variants have at least 85% identity with respect to SEQ ID NO: 164, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. A portion of exon 2 of NRG1 in a fusion with VTCN1 is preferably a sequence conforming to or containing SEQ ID NO: 165, and its allele variants have at least 85% identity with respect to SEQ ID NO: 165, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, a portion of exon 2 of VTCN1 contains or consists of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 164, and contains at least the nucleic acid at position 65. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 164, and may include at least 65 nucleic acids. More preferably, a portion of exon 2 of VTCN1 includes or follows SEQ ID NO: 164 or its allele variant. Such short polynucleotide sequences are particularly useful for detecting the presence of a larger polynucleotide fusion between VTCN1 and NRG1, and for establishing that such a fusion is an intraframe oncogenic fusion containing the EGF-like domain of NRG1.

[0164] Preferably, any VTCN1-NRG1 polynucleotide fusion provided herein is an intraframe fusion of VTCN1 and NRG1. More preferably, the fusion is an intraframe fusion comprising exon 2 or a portion of exon 2 of VTCN1 and exon 2 of NRG1 or a portion of exon 2 of NRG1. The intraframe fusion is preferably the fusion of SEQ ID NO: 166, or an allele variant thereof having at least 85% identity thereto, preferably at least 90%, 92%, 94%, 96%, or 98% identity thereto.

[0165] In alternatively preferred embodiments, the polynucleotide comprising a portion of exon 2 of VTCN1 fused with a portion of exon 2 of NRG1 comprises 2 to about 10, about 20, about 30, or up to about 40, or all consecutive nucleic acids from SEQ ID NO: 166, including the nucleic acids at positions 65 and 66. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids in SEQ ID NO: 166, and may include nucleic acids at positions 65 and 66. SEQ ID NO: 166 includes a junction between VTCN1 and NRG1, and in particular, the junction is between the nucleic acid at position 65 derived from VTCN1 and the nucleic acid at position 66 derived from NRG1. Preferably, the polynucleotide containing a portion of exon 2 of VTCN1 fused with a portion of exon 2 of NRG1 has the polynucleotide sequence of SEQ ID NO: 166, or an allele variant thereof. Preferably, the portion of exon 2 of NRG1 in the fusion with VTCN1 contains or consists of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 126 or its allele variant, and contains at least one nucleic acid. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 of the nucleic acids in SEQ ID NO: 126, and may include at least the nucleic acid at position 1.

[0166] In preferred embodiments, a polynucleotide is provided that includes a polynucleotide according to SEQ ID NO: 166, or a polynucleotide comprising about 20, about 30, about 40, or all consecutive nucleic acids from SEQ ID NO: 166, preferably comprising nucleic acids at positions 65 and 66. The number of consecutive nucleic acids may be 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all nucleic acids from SEQ ID NO: 166, preferably comprising nucleic acids at least at positions 65 and 66.

[0167] Preferably, a polynucleotide containing a portion of exon 2 of VTCN1, or a portion of exon 2 of VTCN1 fused with an allele variant thereof, further contains or encodes the EGF-like domain of NRG1. Abnormal cells containing VTCN1 or polynucleotide fusions expressing the polypeptide fusion contain or encode the EGF-like domain of NRG1. For rapid detection, diagnosis, or specific purposes, it may be sufficient to indicate that the fusion junction between VTCN1 and NRG1 is within a frame and occurs at a position that contains the EGF-like domain of NRG1. The EGF-like domain is preferably an EGF-like domain according to SEQ ID NO: 163, or an allele variant thereof having at least 85% identity to SEQ ID NO: 163, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity thereto.

[0168] Preferably, a portion of exon 2 of VTCN1 or its allele variant is 5' relative to exon 2 of NRG1 or its allele variant. This orientation at the nucleic acid level results in a fusion polypeptide product containing the N-terminus of VTCN1 and the C-terminus of NRG1. Furthermore, the VTCN1-NRG1 polynucleotide fusion provided herein produces a protein fusion in which the portion from the N-terminus to the fusion junction is a polypeptide sequence from VTCN1, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, with the NRG1 portion also providing its EGF-like domain. Thus, the VTCN1-NRG1 fusion protein retains the EGF-like domain of NRG1 and retains the ability to promote the growth and survival of human cancers, particularly subsets of adenocarcinomas.

[0169] When present in abnormal cells of a patient or subject, the polynucleotide fusion preferably further comprises any sequence 5' from exon 2 of VTCN1 and any sequence 3' from exon 2 of NRG1, and it may be sufficient to have at least SEQ ID NOs. 169 and 126 present to enable detection of the fusion junction using a polynucleotide-based detection assay. Any sequence 5' from exon 2 of VTCN1 comprises or consists of SEQ ID NOs. 168 (or any allele variant of SEQ ID NOs. 168), and any sequence 3' from exon 2 of NRG1 comprises or consists of one or all of SEQ ID NOs. 127-137 (or any allele variant of SEQ ID NOs. 127-137).

[0170] CDH1-NRG1 polynucleotide fusion A polynucleotide fusion is also provided, comprising a portion of exon 11 of CDH1 fused with a portion of exon 2 of NRG1. The exon 11 of CDH1 is preferably the exon of SEQ ID NO: 198 or an allele variant of SEQ ID NO: 198, and the exon 2 of NRG1 is preferably the exon of SEQ ID NO: 126 or an allele variant of SEQ ID NO: 126.

[0171] When present in abnormal cells of a patient or subject, the polynucleotide fusion preferably further comprises any sequence 5' from exon 11 of CDH1 and any sequence 3' from exon 2 of NRG1, and it may be sufficient to have at least SEQ ID NOs. 198 and 126 present to enable detection of the fusion junction using a polynucleotide-based detection assay. Any sequence 5' from exon 11 of CDH1 comprises or consists of one or all of SEQ ID NOs. 188-197 (or any allele variant of SEQ ID NOs. 188-197), and any sequence 3' from exon 2 of NRG1 comprises or consists of one or all of SEQ ID NOs. 127-137 (or any allele variant of SEQ ID NOs. 127-137).

[0172] Preferably, the allele variant of exon 11 of CDH1 has at least 85% identity with SEQ ID NO: 198, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity, and the allele variant of exon 2 of NRG1 has at least 85% identity with SEQ ID NO: 126, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0173] Preferably, a portion of exon 11 of CDH1 contains or conforms to sequence number 184, and the allele variant has at least 85% identity with respect to sequence number 184, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. A portion of exon 2 of NRG1 in the fusion with CDH1 is preferably a sequence conforming to or containing sequence number 185, and the allele variant has at least 85% identity with respect to sequence number 185, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, a portion of exon 11 of CDH1 contains or consists of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from sequence number 184, and contains at least the nucleic acid at position 119. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 184, and may include at least 119 nucleic acids. More preferably, a portion of exon 11 of CDH1 includes or follows SEQ ID NO: 184 or its allele variant. Such short polynucleotide sequences are particularly useful for detecting the presence of a larger polynucleotide fusion between CDH1 and NRG1, and for establishing that such a fusion is an intraframe oncogenic fusion containing the EGF-like domain of NRG1.

[0174] Alternatively, a portion of exon 11 of CDH1 contains or comprises SEQ ID NO: 198 (or an allele variant of SEQ ID NO: 198) and comprises at least 146 nucleic acids. Preferably, a portion of exon 11 of CDH1 contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 198 or its allele variants, and comprises at least 146 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 198, and include at least 146 nucleic acids. In this alternative example, a portion of exon 11 of CDH1 more preferably includes or follows SEQ ID NO: 198 or its allele variant.

[0175] Preferably, any CDH1-NRG1 polynucleotide fusion provided herein is an intraframe fusion of CDH1 and NRG1. More preferably, the fusion is an intraframe fusion comprising exon 11 or a portion of exon 2 of CDH1 and exon 2 of NRG1 or a portion of exon 2 of NRG1. The intraframe fusion is preferably the fusion of SEQ ID NO: 186, or an allele variant thereof having at least 85% identity thereto, preferably at least 90%, 92%, 94%, 96%, or 98% identity thereto.

[0176] In alternatively preferred embodiments, the polynucleotide comprising a portion of exo 11 of CDH1 fused with a portion of exon 2 of NRG1 comprises 2 to about 10, about 20, about 30, or up to about 40, or all consecutive nucleic acids from SEQ ID NO: 186, including the nucleic acids at positions 119 and 120. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids in sequence number 186, and includes at least the nucleic acids at positions 119 and 120. Sequence number 186 includes a junction between CDH1 and NRG1, and in particular, the junction is between the nucleic acid at position 119 derived from CDH1 and the nucleic acid at position 120 derived from NRG1. Preferably, the polynucleotide containing a portion of exon 11 of CDH1 fused with a portion of exon 2 of NRG1 has the polynucleotide sequence of SEQ ID NO: 186, or an allele variant thereof.

[0177] In preferred embodiments, a polynucleotide is provided that includes a polynucleotide according to SEQ ID NO: 186, or a polynucleotide comprising about 20, about 30, about 40, or all consecutive nucleic acids from SEQ ID NO: 186, preferably comprising nucleic acids at positions 119 and 120. The number of consecutive nucleic acids may be 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all nucleic acids from SEQ ID NO: 186, preferably comprising nucleic acids at least at positions 119 and 120.

[0178] Preferably, a polynucleotide comprising a portion of exon 2 of NRG1, or a portion of exon 11 of CDH1 fused with an allele variant thereof, or an allele variant thereof, further comprises a portion of a longer polynucleotide that comprises or encodes the EGF-like domain of NRG1. Abnormal cells comprising CDH1 or polynucleotide fusions expressing a polypeptide fusion contain or encode the EGF-like domain of NRG1. For rapid detection, diagnosis, or specific purposes, it may be sufficient to indicate that the fusion junction between CDH1 and NRG1 is within a frame and occurs at a position that contains the EGF-like domain of NRG1. The EGF-like domain is preferably an EGF-like domain according to SEQ ID NO: 163, or an allele variant thereof having at least 85% identity to SEQ ID NO: 163, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity thereto.

[0179] Preferably, exon 11 of CDH1 or a portion of its allele variant is 5' relative to exon 2 of NRG1 or a portion of its allele variant. This orientation at the nucleic acid level results in a fusion polypeptide product containing the N-terminus of CDH1 and the C-terminus of NRG1. Furthermore, the CDH1-NRG1 polynucleotide fusion provided herein produces a protein fusion in which the portion from the N-terminus to the fusion junction is a polypeptide sequence from CDH1, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, with the NRG1 portion also providing its EGF-like domain. Thus, the CDH1-NRG1 fusion protein retains the EGF-like domain of NRG1 and retains the ability to promote the growth and survival of human cancers, particularly adenocarcinomas, more specifically subsets of pancreatic ductal adenocarcinoma.

[0180] CXADR-NRG1 polynucleotide fusion A polynucleotide fusion is also provided, comprising a portion of exon 1 of CXADR fused with a portion of exon 2 of NRG1. The exon 1 of CXADR is preferably the exon of SEQ ID NO: 219 or an allele variant of SEQ ID NO: 219, and the exon 2 of NRG1 is preferably the exon of SEQ ID NO: 126 or an allele variant of SEQ ID NO: 126.

[0181] If present in the abnormal cells of a patient or subject, the polynucleotide fusion preferably further comprises any sequence 5' from exon 1 of CXADR and any sequence 3' from exon 2 of NRG1, and it may be sufficient to have at least SEQ ID NOs. 219 and 126 present to enable detection of the fusion junction using a polynucleotide-based detection assay. Any sequence 3' from exon 2 of NRG1 comprises or consists of one or all of SEQ ID NOs. 127-137 (or any allele variants of SEQ ID NOs. 127-137).

[0182] Preferably, the allele variant of exon 1 of CXADR has at least 85% identity with SEQ ID NO: 219, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity, and the allele variant of exon 2 of NRG1 has at least 85% identity with SEQ ID NO: 126, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0183] Preferably, a portion of exon 1 of CXADR contains or conforms to SEQ ID NO: 215, and its allele variants have at least 85% identity with respect to SEQ ID NO: 215, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. A portion of exon 2 of NRG1 in the fusion with CXADR is preferably a sequence conforming to or containing SEQ ID NO: 216, and its allele variants have at least 85% identity with respect to SEQ ID NO: 216, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, a portion of exon 1 of CXADR contains or consists of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 215, and contains at least 43 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 215, and include at least 43 nucleic acids. More preferably, a portion of exon 1 of CXADR includes or follows SEQ ID NO: 215 or its allele variant. Such short polynucleotide sequences are particularly useful for detecting the presence of larger polynucleotide fusions between CXADR and NRG1, and for establishing that such fusions are intraframe oncogenic fusions containing the EGF-like domain of NRG1.

[0184] Alternatively, a portion of exon 1 of CXADR contains or comprises SEQ ID NO: 219 (or an allele variant of SEQ ID NO: 219) and comprises at least 130 nucleic acids. Preferably, a portion of exon 1 of CXADR contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 219 or its allele variants, and comprises at least 130 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 219, and may include at least 130 nucleic acids. In this alternative example, a portion of exon 1 of CXADR more preferably includes or follows SEQ ID NO: 219 or its allele variant.

[0185] Preferably, any CXADR-NRG1 polynucleotide fusion provided herein is an intraframe fusion of CXADR and NRG1. More preferably, the fusion is an intraframe fusion comprising a portion of exon 1 or exon 2 of CXADR and an exon 2 of NRG1 or a portion of exon 2 of NRG1. The intraframe fusion is preferably the fusion of SEQ ID NO: 217, or an allele variant thereof having at least 85% identity thereto, preferably at least 90%, 92%, 94%, 96%, or 98% identity thereto.

[0186] In alternatively preferred embodiments, the polynucleotide comprising a portion of exon 1 of CXADR fused with a portion of exon 2 of NRG1 comprises 2 to about 10, about 20, about 30, or up to about 40, or all consecutive nucleic acids from SEQ ID NO: 217, including the nucleic acids at positions 43 and 44. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids in Sequence ID No. 217, and includes nucleic acids at least at positions 43 and 44. Sequence ID No. 217 includes a junction between CXADR and NRG1, and in particular, the junction is between the nucleic acid at position 43 derived from CXADR and the nucleic acid at position 44 derived from NRG1. Preferably, the polynucleotide containing a portion of exon 1 of CXADR fused with a portion of exon 2 of NRG1 has the polynucleotide sequence of SEQ ID NO: 217, or an allele variant thereof. Preferably, the portion of exon 2 of NRG1 in the fusion with CXADR contains or consists of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 126 or its allele variant, and contains at least one nucleic acid. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 of the nucleic acids in SEQ ID NO: 126, and may include at least the nucleic acid at position 1.

[0187] In preferred embodiments, a polynucleotide is provided that includes a polynucleotide according to SEQ ID NO: 217, or a polynucleotide comprising about 20, about 30, about 40, or all consecutive nucleic acids from SEQ ID NO: 217, preferably comprising nucleic acids at positions 43 and 44. The number of consecutive nucleic acids may be 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all nucleic acids from SEQ ID NO: 217, preferably comprising nucleic acids at least at positions 43 and 44.

[0188] Preferably, a polynucleotide comprising a portion of exon 2 of NRG1, or a portion of exon 1 of CXADR fused with an allele variant thereof, or an allele variant thereof, further comprises a portion of a longer polynucleotide that comprises or encodes the EGF-like domain of NRG1. Abnormal cells comprising CXADR or polynucleotide fusions expressing the polypeptide fusion contain or encode the EGF-like domain of NRG1. For rapid detection, diagnosis, or specific purposes, it may be sufficient to indicate that the fusion junction between CXADR and NRG1 is within a frame and occurs at a position that contains the EGF-like domain of NRG1. The EGF-like domain is preferably an EGF-like domain according to SEQ ID NO: 163, or an allele variant thereof having at least 85% identity to SEQ ID NO: 163, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity thereto.

[0189] Preferably, exon 1 of CXADR or a portion of its allele variant is 5' relative to exon 2 of NRG1 or a portion of its allele variant. This orientation at the nucleic acid level results in a fusion polypeptide product containing the N-terminus of CXADR and the C-terminus of NRG1. Furthermore, the CXADR-NRG1 polynucleotide fusion provided herein produces a protein fusion in which the portion from the N-terminus to the fusion junction is a polypeptide sequence from CXADR, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, with the NRG1 portion also providing its EGF-like domain. Thus, the CXADR-NRG1 fusion protein retains the EGF-like domain of NRG1 and retains the ability to promote the growth and survival of human cancers, particularly a subset of colorectal cancer.

[0190] GTF2E2-NRG1 polynucleotide fusion A polynucleotide fusion is also provided, comprising a portion of exon 2 of GTF2E2 fused with a portion of exon 2 of NRG1. The exon 2 of GTF2E2 is preferably the exon of SEQ ID NO: 236 or an allele variant of SEQ ID NO: 236, and the exon 2 of NRG1 is preferably the exon of SEQ ID NO: 126 or an allele variant of SEQ ID NO: 126.

[0191] When present in abnormal cells of a patient or subject, the polynucleotide fusion preferably further comprises any sequence 5' from exon 2 of GTF2E2 and any sequence 3' from exon 2 of NRG1, and it may be sufficient to have at least SEQ ID NOs. 236 and 126 present to enable detection of the fusion junction using a polynucleotide-based detection assay. Any sequence 5' from exon 2 of GTF2E2 comprises or consists of one or all of SEQ ID NOs. 235 (or any allele variant of SEQ ID NOs. 235), and any sequence 3' from exon 2 of NRG1 comprises or consists of one or all of SEQ ID NOs. 127-137 (or any allele variant of SEQ ID NOs. 127-137).

[0192] Preferably, the exon 2 allele variant of GTF2E2 has at least 85% identity with SEQ ID NO: 236, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity, and the exon 2 allele variant of NRG1 has at least 85% identity with SEQ ID NO: 126, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0193] Preferably, a portion of exon 2 of GTF2E2 contains or conforms to SEQ ID NO: 231, and its allele variants have at least 85% identity with respect to SEQ ID NO: 231, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. A portion of exon 2 of NRG1 in a fusion with GTF2E2 is preferably a sequence conforming to or containing SEQ ID NO: 232, and its allele variants have at least 85% identity with respect to SEQ ID NO: 232, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, a portion of exon 2 of GTF2E2 contains or consists of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 231, and contains at least 141 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 231, and include at least 141 nucleic acids. More preferably, a portion of exon 2 of GTF2E2 includes or follows SEQ ID NO: 231 or its allele variant. Such short polynucleotide sequences are particularly useful for detecting the presence of a larger polynucleotide fusion between GTF2E2 and NRG1, and for establishing that such a fusion is an intraframe oncogenic fusion containing the EGF-like domain of NRG1.

[0194] Alternatively, a portion of exon 2 of GTF2E2 contains or comprises SEQ ID NO: 236 (or an allele variant of SEQ ID NO: 236) and comprises at least 170 nucleic acids. Preferably, a portion of exon 2 of GTF2E2 contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 236 or its allele variants, and comprises at least 170 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids, and may include at least 170 nucleic acids. In this alternative example, a portion of exon 2 of GTF2E2 more preferably includes or follows sequence number 236 or its allele variant. Preferably, the portion of exon 2 of NRG1 in the fusion with GTF2E2 contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 126 or its allele variants, and contains at least the nucleic acid at position 1. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 of the nucleic acids in SEQ ID NO: 126, and may include at least the nucleic acid at position 1.

[0195] Preferably, any GTF2E2-NRG1 polynucleotide fusion provided herein is an intraframe fusion of GTF2E2 and NRG1. More preferably, the fusion is an intraframe fusion comprising exon 2 or a portion of exon 2 of GTF2E2 and exon 2 or a portion of exon 2 of NRG1. The intraframe fusion is preferably the fusion of Sequence ID No. 233, or an allele variant thereof having at least 85% identity thereto, preferably at least 90%, 92%, 94%, 96%, or 98% identity thereto.

[0196] In alternatively preferred embodiments, the polynucleotide comprising a portion of exon 2 of GTF2E2 fused with a portion of exon 2 of NRG1 comprises 2 to about 10, about 20, about 30, or up to about 40, or all consecutive nucleic acids from SEQ ID NO: 233, including the nucleic acids at positions 141 and 142. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids in sequence number 233, and include at least the nucleic acids at positions 141 and 142. Sequence number 233 includes a junction between GTF2E2 and NRG1, and in particular, the junction is between the nucleic acid at position 141 derived from GTF2E2 and the nucleic acid at position 142 derived from NRG1. Preferably, the polynucleotide containing a portion of exon 2 of GTF2E2 fused with a portion of exon 2 of NRG1 has the polynucleotide sequence of SEQ ID NO: 233, or an allele variant thereof.

[0197] In preferred embodiments, a polynucleotide is provided that includes a polynucleotide according to SEQ ID NO: 233, or a polynucleotide comprising about 20, about 30, about 40, or all consecutive nucleic acids from SEQ ID NO: 233, preferably comprising nucleic acids at positions 141 and 142. The number of consecutive nucleic acids may be 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all nucleic acids from SEQ ID NO: 233, preferably comprising nucleic acids at least at positions 141 and 142.

[0198] Preferably, a polynucleotide containing a portion of exon 2 of NRG1, or a portion of exon 2 of GTF2E2 fused with an allele variant thereof, or an allele variant thereof, further contains or encodes the EGF-like domain of NRG1. Abnormal cells containing GTF2E2 or polynucleotide fusions expressing a polypeptide fusion contain or encode the EGF-like domain of NRG1. For rapid detection, diagnosis, or specific purposes, it may be sufficient to indicate that the fusion junction between GTF2E2 and NRG1 is within a frame and occurs at a position that contains the EGF-like domain of NRG1. The EGF-like domain is preferably an EGF-like domain according to SEQ ID NO: 163, or an allele variant thereof having at least 85% identity to SEQ ID NO: 163, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity thereto.

[0199] Preferably, a portion of exon 2 of GTF2E2 or its allele variant is 5' relative to a portion of exon 2 of NRG1 or its allele variant. This orientation at the nucleic acid level results in a fusion polypeptide product containing the N-terminus of GTF2E2 and the C-terminus of NRG1. The GTF2E2-NRG1 polynucleotide fusion provided herein also produces a protein fusion, where the portion from the N-terminus to the fusion junction is a polypeptide sequence from GTF2E2, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, with the NRG1 portion also providing its EGF-like domain. Thus, the GTF2E2-NRG1 fusion protein retains the EGF-like domain of NRG1 and retains the ability to promote the growth and survival of human cancers, particularly adenocarcinomas, more specifically subsets of (metastatic) mammary carcinoma NOS.

[0200] CSMD1-NRG1 polynucleotide fusion A polynucleotide fusion is also provided, comprising a portion of exon 23 of CSMD1 fused with a portion of exon 6 of NRG1. The exon 23 of CSMD1 is preferably the exon of SEQ ID NO: 279 or the allele variant of SEQ ID NO: 279, and the exon 6 of NRG1 is preferably the exon of SEQ ID NO: 130 or the allele variant of SEQ ID NO: 130.

[0201] When present in abnormal cells of a patient or subject, the polynucleotide fusion preferably further comprises any sequence 5' from exon 23 of CSMD1 and any sequence 3' from exon 6 of NRG1, and it may be sufficient to have at least SEQ ID NOs. 279 and 130 to enable detection of the fusion junction using a polynucleotide-based detection assay. Any sequence 5' from exon 23 of CSMD1 comprises or consists of one or all of SEQ ID NOs. 257-278 (or any allele variant of SEQ ID NOs. 257-278), and any sequence 3' from exon 6 of NRG1 comprises or consists of one or all of SEQ ID NOs. 131-137 (or any allele variant of SEQ ID NOs. 131-137).

[0202] Preferably, the allele variant of exon 23 of CSMD1 has at least 85% identity with SEQ ID NO: 279, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity, and the allele variant of exon 6 of NRG1 has at least 85% identity with SEQ ID NO: 130, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0203] Preferably, a portion of exon 23 of CSMD1 contains or conforms to SEQ ID NO: 253, and the allele variant has at least 85% identity with respect to SEQ ID NO: 253, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. A portion of exon 6 of NRG1 in the fusion with CSMD1 is preferably a sequence conforming to or containing SEQ ID NO: 254, and the allele variant has at least 85% identity with respect to SEQ ID NO: 254, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, a portion of exon 23 of CSMD1 contains or consists of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 253, and contains at least 88 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 253, and include at least 88 nucleic acids. More preferably, a portion of exon 23 of CSMD1 includes or follows SEQ ID NO: 253 or its allele variant. Such short polynucleotide sequences are particularly useful for detecting the presence of larger polynucleotide fusions between CSMD1 and NRG1, and for establishing that such fusions are intraframe oncogenic fusions containing the EGF-like domain of NRG1.

[0204] Alternatively, a portion of exon 23 of CSMD1 contains or comprises SEQ ID NO: 279 (or an allele variant of SEQ ID NO: 279) and comprises at least 157 nucleic acids. Preferably, a portion of exon 23 of CSMD1 contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 279 or its allele variants, and comprises at least 157 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 279, and may include at least 157 nucleic acids. In this alternative example, a portion of exon 23 of CSMD1 more preferably includes or follows SEQ ID NO: 279 or its allele variant. Preferably, a portion of exon 6 of NRG1 in the fusion with CSMD1 contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 130 or its allele variants, and contains at least the nucleic acid at position 1. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 of the nucleic acids in SEQ ID NO: 130, and may include at least the nucleic acid at position 1.

[0205] Preferably, any CSMD1-NRG1 polynucleotide fusion provided herein is an intraframe fusion of CSMD1 and NRG1. More preferably, the fusion is an intraframe fusion comprising a portion of exon 23 or exon 6 of CSMD1 and an exon 6 of NRG1 or a portion of exon 6 of NRG1. The intraframe fusion is preferably the fusion of SEQ ID NO: 255, or an allele variant thereof having at least 85% identity thereto, preferably at least 90%, 92%, 94%, 96%, or 98% identity thereto.

[0206] In alternatively preferred embodiments, the polynucleotide comprising a portion of exon 23 of CSMD1 fused with a portion of exon 6 of NRG1 comprises 2 to about 10, about 20, about 30, or up to about 40, or all consecutive nucleic acids from SEQ ID NO: 255, including the nucleic acids at positions 88 and 89. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids in Sequence ID No. 255, and includes nucleic acids at least at positions 88 and 89. Sequence ID No. 255 includes a junction between CSMD1 and NRG1, and in particular, the junction is between the nucleic acid at position 88 derived from CSMD1 and the nucleic acid at position 89 derived from NRG1. Preferably, the polynucleotide containing a portion of exon 23 of CSMD1 fused with a portion of exon 6 of NRG1 has the polynucleotide sequence of SEQ ID NO: 255, or an allele variant thereof.

[0207] In preferred embodiments, a polynucleotide is provided that includes a polynucleotide according to SEQ ID NO: 255, or a polynucleotide comprising about 20, about 30, about 40, or all consecutive nucleic acids from SEQ ID NO: 255, preferably comprising nucleic acids at positions 88 and 89. The number of consecutive nucleic acids may be 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all nucleic acids from SEQ ID NO: 255, preferably comprising nucleic acids at least at positions 88 and 89.

[0208] Preferably, a polynucleotide comprising a portion of exon 6 of NRG1, or a portion of exon 23 of CSMD1 fused with an allele variant thereof, or an allele variant thereof, further comprises a portion of a longer polynucleotide that comprises or encodes the EGF-like domain of NRG1. Abnormal cells comprising CSMD1 or polynucleotide fusions expressing the polypeptide fusion contain or encode the EGF-like domain of NRG1. For rapid detection, diagnosis, or specific purposes, it may be sufficient to indicate that the fusion junction between CSMD1 and NRG1 is within a frame and occurs at a position that contains the EGF-like domain of NRG1. The EGF-like domain is preferably an EGF-like domain according to SEQ ID NO: 163, or an allele variant thereof having at least 85% identity to SEQ ID NO: 163, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity thereto.

[0209] Preferably, exon 23 of CSMD1 or a portion of its allele variant is 5' relative to exon 6 of NRG1 or a portion of its allele variant. This orientation at the nucleic acid level results in a fusion polypeptide product containing the N-terminus of CSMD1 and the C-terminus of NRG1. The CSMD1-NRG1 polynucleotide fusion provided herein also produces a protein fusion, where the portion from the N-terminus to the fusion junction is a polypeptide sequence from CSMD1, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, with the NRG1 portion also providing its EGF-like domain. Thus, the CSMD1-NRG1 fusion protein retains the EGF-like domain of NRG1 and retains the ability to promote the growth and survival of human cancers, particularly adenocarcinomas, and more specifically, subsets of pancreatic ductal adenocarcinoma.

[0210] PTN-NRG1 polynucleotide fusion A polynucleotide fusion is also provided, comprising a portion of exon 4 of PTN fused with a portion of exon 2 of NRG1. The exon 4 of PTN is preferably the exon of SEQ ID NO: 318 or an allele variant of SEQ ID NO: 318, and the exon 2 of NRG1 is preferably the exon of SEQ ID NO: 126 or an allele variant of SEQ ID NO: 126.

[0211] When present in abnormal cells of a patient or subject, the polynucleotide fusion preferably further comprises any sequence 5' from exon 4 of PTN and any sequence 3' from exon 2 of NRG1, and it may be sufficient to have at least SEQ ID NOs. 318 and 126 present to enable detection of the fusion junction using a polynucleotide-based detection assay. Any sequence 5' from exon 4 of PTN comprises or consists of one or all of SEQ ID NOs. 315-317 (or any allele variant of SEQ ID NOs. 315-317), and any sequence 3' from exon 2 of NRG1 comprises or consists of one or all of SEQ ID NOs. 127-137 (or any allele variant of SEQ ID NOs. 127-137).

[0212] Preferably, the allele variant of exon 4 of PTN has at least 85% identity with SEQ ID NO: 318, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity, and the allele variant of exon 2 of NRG1 has at least 85% identity with SEQ ID NO: 126, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0213] Preferably, a portion of exon 4 of PTN contains or conforms to sequence number 311, and its allele variants have at least 85% identity with respect to sequence number 311, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. A portion of exon 2 of NRG1 in the fusion with PTN is preferably a sequence conforming to or containing sequence number 312, and its allele variants have at least 85% identity with respect to sequence number 312, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, a portion of exon 4 of PTN contains or consists of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from sequence number 311, and contains at least 102 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 311, and include at least 102 nucleic acids. More preferably, a portion of exon 4 of PTN includes or follows SEQ ID NO: 311 or its allele variant. Such short polynucleotide sequences are particularly useful for detecting the presence of larger polynucleotide fusions between PTN and NRG1, and for establishing that such fusions are intraframe oncogenic fusions containing the EGF-like domain of NRG1.

[0214] Alternatively, a portion of exon 4 of PTN may contain or consist of SEQ ID NO: 318 (or an allele variant of SEQ ID NO: 318) and include at least 162 nucleic acids. Preferably, a portion of exon 4 of PTN may contain or consist of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 318 or its allele variants, and include at least 162 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 318, and include at least 162 nucleic acids. In this alternative example, a portion of exon 4 of PTN more preferably includes or follows SEQ ID NO: 318 or its allele variant. Preferably, a portion of exon 2 of NRG1 in the fusion with PTN contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 126 or its allele variant, and contains at least one nucleic acid. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 of the nucleic acids in SEQ ID NO: 126, and may include at least the nucleic acid at position 1.

[0215] Preferably, any PTN-NRG1 polynucleotide fusion provided herein is an intraframe fusion of PTN and NRG1. More preferably, the fusion is an intraframe fusion comprising a portion of exon 4 or exon 2 of PTN and an exon 2 of NRG1 or a portion of exon 2 of NRG1. The intraframe fusion is preferably the fusion of SEQ ID NO: 313, or an allele variant thereof having at least 85% identity thereto, preferably at least 90%, 92%, 94%, 96%, or 98% identity thereto.

[0216] In alternatively preferred embodiments, the polynucleotide comprising a portion of exon 4 of PTN fused with a portion of exon 2 of NRG1 comprises 2 to about 10, about 20, about 30, or up to about 40, or all consecutive nucleic acids from SEQ ID NO: 313, including the nucleic acids at positions 102 and 103. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids in SEQ ID NO: 313, and may include at least the nucleic acids at positions 102 and 103. SEQ ID NO: 313 includes a junction between PTN and NRG1, and in particular, the junction is between the nucleic acid at position 102 derived from PTN and the nucleic acid at position 103 derived from NRG1. Preferably, the polynucleotide containing a portion of exon 4 of PTN fused with a portion of exon 2 of NRG1 has the polynucleotide sequence of SEQ ID NO: 313, or an allele variant thereof.

[0217] In a preferred embodiment, a polynucleotide is provided that includes a polynucleotide according to SEQ ID NO: 313, or a polynucleotide comprising about 20, about 30, about 40, or all consecutive nucleic acids from SEQ ID NO: 313, preferably comprising nucleic acids at positions 102 and 103. The number of consecutive nucleic acids may be 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all nucleic acids from SEQ ID NO: 313, preferably comprising nucleic acids at least at positions 102 and 103.

[0218] Preferably, a polynucleotide comprising a portion of exon 2 of NRG1, or a portion of exon 4 of PTN fused with an allele variant thereof, or an allele variant thereof, further comprises a portion of a longer polynucleotide that comprises or encodes the EGF-like domain of NRG1. Abnormal cells containing PTN or polynucleotide fusions expressing a polypeptide fusion contain or encode the EGF-like domain of NRG1. For rapid detection, diagnosis, or specific purposes, it may be sufficient to indicate that the fusion junction between PTN and NRG1 is within a frame and occurs at a position that contains the EGF-like domain of NRG1. The EGF-like domain is preferably an EGF-like domain according to SEQ ID NO: 163, or an allele variant thereof having at least 85% identity to SEQ ID NO: 163, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity thereto.

[0219] Preferably, exon 4 of PTN or a portion of its allele variant is 5' relative to exon 2 of NRG1 or a portion of its allele variant. This orientation at the nucleic acid level results in a fusion polypeptide product containing the N-terminus of PTN and the C-terminus of NRG1. Furthermore, the PTN-NRG1 polynucleotide fusion provided herein produces a protein fusion in which the portion from the N-terminus to the fusion junction is a polypeptide sequence from PTN, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, with the NRG1 portion also providing its EGF-like domain. Thus, the PTN-NRG1 fusion protein retains the EGF-like domain of NRG1 and retains the ability to promote the growth and survival of human cancers, particularly adenocarcinomas, more specifically subsets of pancreatic ductal adenocarcinoma.

[0220] ST14-NRG1 polynucleotide fusion A polynucleotide fusion is also provided, comprising a portion of exon 11 of ST14 fused with a portion of exon 6 of NRG1. The exon 11 of ST14 is preferably the exon of SEQ ID NO: 342 or an allele variant of SEQ ID NO: 342, and the exon 6 of NRG1 is preferably the exon of SEQ ID NO: 130 or an allele variant of SEQ ID NO: 130.

[0221] When present in abnormal cells of a patient or subject, the polynucleotide fusion preferably further comprises any sequence 5' from exon 11 of ST14 and any sequence 3' from exon 6 of NRG1, and it may be sufficient to have at least SEQ ID NOs. 342 and 130 to enable detection of the fusion junction using a polynucleotide-based detection assay. Any sequence 5' from exon 11 of ST14 comprises or consists of one or all of SEQ ID NOs. 332-341 (or any allele variant of SEQ ID NOs. 332-341), and any sequence 3' from exon 6 of NRG1 comprises or consists of one or all of SEQ ID NOs. 131-137 (or any allele variant of SEQ ID NOs. 131-137).

[0222] Preferably, the allele variant of exon 11 of ST14 has at least 85% identity with SEQ ID NO: 342, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity, and the allele variant of exon 6 of NRG1 has at least 85% identity with SEQ ID NO: 130, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0223] Preferably, a portion of exon 11 of ST14 contains or conforms to sequence number 328, and its allele variants have at least 85% identity with respect to sequence number 328, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. A portion of exon 6 of NRG1 in the fusion with ST14 is preferably a sequence conforming to or containing sequence number 329, and its allele variants have at least 85% identity with respect to sequence number 329, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, a portion of exon 11 of ST14 contains or consists of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from sequence number 328, and contains at least the nucleic acid at position 95. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 328, and may include at least 95 nucleic acids. More preferably, a portion of exon 11 of ST14 includes or follows SEQ ID NO: 328 or its allele variant. Such short polynucleotide sequences are particularly useful for detecting the presence of larger polynucleotide fusions between ST14 and NRG1, and for establishing that such fusions are intraframe oncogenic fusions containing the EGF-like domain of NRG1.

[0224] Alternatively, a portion of exon 11 of ST14 contains or comprises SEQ ID NO: 342 (or an allele variant of SEQ ID NO: 342) and includes at least 131 nucleic acids. Preferably, a portion of exon 11 of ST14 contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 342 or its allele variants, and includes at least 131 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 342, and include at least 131 nucleic acids. In this alternative example, a portion of exon 11 of ST14 more preferably includes or follows SEQ ID NO: 342 or its allele variant. Preferably, the portion of exon 6 of NRG1 in the fusion with ST14 contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 130 or its allele variants, and contains at least the nucleic acid at position 1. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 of the nucleic acids in SEQ ID NO: 130, and may include at least the nucleic acid at position 1.

[0225] Preferably, any ST14-NRG1 polynucleotide fusion provided herein is an intraframe fusion of ST14 and NRG1. More preferably, the fusion is an intraframe fusion comprising a portion of exon 11 or exon 6 of ST14 and an exon 6 of NRG1 or a portion of exon 6 of NRG1. The intraframe fusion is preferably the fusion of SEQ ID NO: 330, or an allele variant thereof having at least 85% identity thereto, preferably at least 90%, 92%, 94%, 96%, or 98% identity thereto.

[0226] In alternatively preferred embodiments, the polynucleotide comprising a portion of exon 11 of ST14 fused with a portion of exon 6 of NRG1 comprises 2 to about 10, about 20, about 30, or up to about 40, or all consecutive nucleic acids from SEQ ID NO: 330, including the nucleic acids at positions 95 and 96. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids in SEQ ID NO: 330, and may include nucleic acids at least at positions 95 and 96. SEQ ID NO: 330 includes a junction between ST14 and NRG1, and in particular, the junction is between the nucleic acid at position 95 derived from ST14 and the nucleic acid at position 96 derived from NRG1. Preferably, the polynucleotide containing a portion of exon 11 of ST14 fused with a portion of exon 6 of NRG1 has the polynucleotide sequence of SEQ ID NO: 330, or an allele variant thereof.

[0227] In preferred embodiments, a polynucleotide is provided that includes a polynucleotide according to SEQ ID NO: 330, or a polynucleotide comprising about 20, about 30, about 40, or all consecutive nucleic acids from SEQ ID NO: 330, preferably containing nucleic acids at positions 95 and 96. The number of consecutive nucleic acids may be 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all nucleic acids from SEQ ID NO: 330, preferably containing nucleic acids at least at positions 95 and 96.

[0228] Preferably, a polynucleotide comprising a portion of exon 6 of NRG1, or a portion of exon 11 of ST14 fused with an allele variant thereof, or an allele variant thereof, further comprises a portion of a longer polynucleotide that comprises or encodes the EGF-like domain of NRG1. Abnormal cells comprising ST14 or polynucleotide fusions expressing a polypeptide fusion contain or encode the EGF-like domain of NRG1. For rapid detection, diagnosis, or specific purposes, it may be sufficient to indicate that the fusion junction between ST14 and NRG1 is within a frame and occurs at a position that contains the EGF-like domain of NRG1. The EGF-like domain is preferably an EGF-like domain according to SEQ ID NO: 163, or an allele variant thereof having at least 85% identity to SEQ ID NO: 163, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity thereto.

[0229] Preferably, exon 11 of ST14 or a portion of its allele variant is 5' relative to exon 6 of NRG1 or a portion of its allele variant. This orientation at the nucleic acid level results in a fusion polypeptide product containing the N-terminus of ST14 and the C-terminus of NRG1. The ST14-NRG1 polynucleotide fusion provided herein also produces a protein fusion, where the portion from the N-terminus to the fusion junction is a polypeptide sequence from ST14, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, with the NRG1 portion also providing its EGF-like domain. Thus, the ST14-NRG1 fusion protein retains the EGF-like domain of NRG1 and retains the ability to promote the growth and survival of human cancers, particularly adenocarcinomas, more specifically subsets of pancreatic ductal adenocarcinoma.

[0230] THBS1-NRG1 polynucleotide fusion A polynucleotide fusion is also provided, comprising a portion of exon 9 of THBS1 fused with a portion of exon 6 of NRG1. The exon 9 of THBS1 is preferably the exon of SEQ ID NO: 386 or an allele variant of SEQ ID NO: 386, and the exon 6 of NRG1 is preferably the exon of SEQ ID NO: 130 or an allele variant of SEQ ID NO: 130.

[0231] When present in abnormal cells of a patient or subject, the polynucleotide fusion preferably further comprises any sequence 5' from exon 9 of THBS1 and any sequence 3' from exon 6 of NRG1, and it may be sufficient to have at least SEQ ID NOs. 386 and 130 to enable detection of the fusion junction using a polynucleotide-based detection assay. Any sequence 5' from exon 9 of THBS1 comprises or consists of one or all of SEQ ID NOs. 378-385 (or any allele variant of SEQ ID NOs. 378-385), and any sequence 3' from exon 6 of NRG1 comprises or consists of one or all of SEQ ID NOs. 131-137 (or any allele variant of SEQ ID NOs. 131-137).

[0232] Preferably, the allele variant of exon 9 of THBS1 has at least 85% identity with SEQ ID NO: 386, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity, and the allele variant of exon 6 of NRG1 has at least 85% identity with SEQ ID NO: 130, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0233] Preferably, a portion of exon 9 of THBS1 contains or conforms to SEQ ID NO: 374, and its allele variants have at least 85% identity with respect to SEQ ID NO: 374, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. A portion of exon 6 of NRG1 in the fusion with THBS1 is preferably a sequence conforming to or containing SEQ ID NO: 375, and its allele variants have at least 85% identity with respect to SEQ ID NO: 375, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, a portion of exon 9 of THBS1 contains or consists of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 374, and contains at least 56 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 374, and may include at least 56 nucleic acids. More preferably, a portion of exon 9 of THBS1 includes or follows SEQ ID NO: 374 or its allele variant. Such short polynucleotide sequences are particularly useful for detecting the presence of larger polynucleotide fusions between THBS1 and NRG1, and for establishing that such fusions are intraframe oncogenic fusions containing the EGF-like domain of NRG1.

[0234] Alternatively, a portion of exon 9 of THBS1 may contain or consist of SEQ ID NO: 386 (or an allele variant of SEQ ID NO: 386) and include at least 177 nucleic acids. Preferably, a portion of exon 9 of THBS1 may contain or consist of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 386 or its allele variants, and include at least 177 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 386, and include at least 177 nucleic acids. In this alternative example, a portion of exon 9 of THBS1 more preferably includes or follows SEQ ID NO: 386 or its allele variant. Preferably, a portion of exon 6 of NRG1 in the fusion with THBS1 contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 130 or its allele variants, and contains at least one nucleic acid. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 of the nucleic acids in SEQ ID NO: 130, and may include at least the nucleic acid at position 1.

[0235] Preferably, any THBS1-NRG1 polynucleotide fusion provided herein is an intraframe fusion of THBS1 and NRG1. More preferably, the fusion is an intraframe fusion comprising a portion of exon 9 or exon 6 of THBS1 and an exon 6 of NRG1 or a portion of exon 6 of NRG1. The intraframe fusion is preferably the fusion of SEQ ID NO: 376, or an allele variant thereof having at least 85% identity thereto, preferably at least 90%, 92%, 94%, 96%, or 98% identity thereto.

[0236] In an alternatively preferred embodiment, the polynucleotide comprising a portion of exon 9 of THBS1 fused with a portion of exon 6 of NRG1 comprises 2 to about 10, about 20, about 30, or up to about 40, or all consecutive nucleic acids from SEQ ID NO: 376, including the nucleic acids at positions 56 and 57. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids in Sequence ID No. 376, and may contain nucleic acids at least at positions 56 and 57. Sequence ID No. 376 includes a junction between THBS1 and NRG1, and in particular, the junction is between the nucleic acid at position 56 derived from THBS1 and the nucleic acid at position 57 derived from NRG1. Preferably, the polynucleotide containing a portion of exon 9 of THBS1 fused with a portion of exon 6 of NRG1 has the polynucleotide sequence of SEQ ID NO: 376, or an allele variant thereof.

[0237] In preferred embodiments, a polynucleotide is provided that includes a polynucleotide according to SEQ ID NO: 376, or a polynucleotide comprising about 20, about 30, about 40, or all consecutive nucleic acids from SEQ ID NO: 376, preferably comprising nucleic acids at positions 56 and 57. The number of consecutive nucleic acids may be 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all nucleic acids from SEQ ID NO: 376, preferably comprising nucleic acids at least at positions 56 and 57.

[0238] Preferably, a polynucleotide comprising a portion of exon 6 of NRG1, or a portion of exon 9 of THBS1 fused with an allele variant thereof, or an allele variant thereof, further comprises a portion of a longer polynucleotide that comprises or encodes the EGF-like domain of NRG1. Abnormal cells comprising THBS1 or polynucleotide fusions expressing the polypeptide fusion contain or encode the EGF-like domain of NRG1. For rapid detection, diagnosis, or specific purposes, it may be sufficient to indicate that the fusion junction between THBS1 and NRG1 is within a frame and occurs at a position that contains the EGF-like domain of NRG1. The EGF-like domain is preferably an EGF-like domain according to SEQ ID NO: 163, or an allele variant thereof having at least 85% identity to SEQ ID NO: 163, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity thereto.

[0239] Preferably, exon 9 of THBS1 or a portion of its allele variant is 5' relative to exon 6 of NRG1 or a portion of its allele variant. This orientation at the nucleic acid level results in a fusion polypeptide product containing the N-terminus of THBS1 and the C-terminus of NRG1. Furthermore, the THBS1-NRG1 polynucleotide fusion provided herein produces a protein fusion in which the portion from the N-terminus to the fusion junction is a polypeptide sequence from THBS1, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, with the NRG1 portion also providing its EGF-like domain. Thus, the THBS1-NRG1 fusion protein retains the EGF-like domain of NRG1 and retains the ability to promote the growth and survival of human cancers, particularly adenocarcinomas, more specifically subsets of pancreatic ductal adenocarcinoma.

[0240] AGRN-NRG1 polynucleotide fusion A polynucleotide fusion is also provided, comprising a portion of exon 12 of AGRN fused with a portion of exon 6 of NRG1. The exon 12 of AGRN is preferably the exon of SEQ ID NO: 416 or an allele variant of SEQ ID NO: 416, and the exon 6 of NRG1 is preferably the exon of SEQ ID NO: 130 or an allele variant of SEQ ID NO: 130.

[0241] When present in abnormal cells of a patient or subject, the polynucleotide fusion preferably further comprises any sequence 5' from exon 12 of AGRN and any sequence 3' from exon 6 of NRG1, and it may be sufficient to have at least SEQ ID NOs. 416 and 130 present to enable detection of the fusion junction using a polynucleotide-based detection assay. The any sequence 5' from exon 12 of AGRN comprises or consists of one or all of SEQ ID NOs. 405-415 (or any allele variant of SEQ ID NOs. 405-415), and the any sequence 3' from exon 6 of NRG1 comprises or consists of one or all of SEQ ID NOs. 131-137 (or any allele variant of SEQ ID NOs. 131-137).

[0242] Preferably, the allele variant of exon 12 of AGRN has at least 85% identity with SEQ ID NO: 416, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity, and the allele variant of exon 6 of NRG1 has at least 85% identity with SEQ ID NO: 130, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0243] Preferably, a portion of exon 12 of AGRN contains or conforms to sequence number 401, and its allele variants have at least 85% identity with respect to sequence number 401, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. A portion of exon 6 of NRG1 in the fusion with AGRN is preferably a sequence conforming to or containing sequence number 402, and its allele variants have at least 85% identity with respect to sequence number 402, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, a portion of exon 12 of AGRN contains or consists of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from sequence number 401, and contains at least 106 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 401, and may include at least 106 nucleic acids. More preferably, a portion of exon 12 of AGRN includes or follows SEQ ID NO: 401 or its allele variant. Such short polynucleotide sequences are particularly useful for detecting the presence of larger polynucleotide fusions between AGRN and NRG1 and for establishing that such fusions are intraframe oncogenic fusions containing the EGF-like domain of NRG1.

[0244] Alternatively, a portion of exon 12 of AGRN may contain or consist of SEQ ID NO: 416 (or an allele variant of SEQ ID NO: 416) and include at least 106 nucleic acids. Preferably, a portion of exon 12 of AGRN may contain or consist of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 416 or its allele variants, and include at least 106 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 416, and include at least 106 nucleic acids. In this alternative example, a portion of exon 12 of AGRN more preferably includes or follows SEQ ID NO: 416 or its allele variant. Preferably, a portion of exon 6 of NRG1 in the fusion with AGRN contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 130 or its allele variants, and contains at least one nucleic acid. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 of the nucleic acids in SEQ ID NO: 130, and may include at least the nucleic acid at position 1.

[0245] Preferably, any AGRN-NRG1 polynucleotide fusion provided herein is an intraframe fusion of AGRN and NRG1. More preferably, the fusion is an intraframe fusion comprising exon 12 or a portion of exon 12 of AGRN and exon 6 or a portion of exon 6 of NRG1. The intraframe fusion is preferably the fusion of SEQ ID NO: 403, or an allele variant thereof having at least 85% identity thereto, preferably at least 90%, 92%, 94%, 96%, or 98% identity thereto.

[0246] In alternatively preferred embodiments, the polynucleotide comprising a portion of exon 12 of AGRN fused with a portion of exon 6 of NRG1 comprises 2 to about 10, about 20, about 30, or up to about 40, or all consecutive nucleic acids from SEQ ID NO: 403, including the nucleic acids at positions 106 and 107. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids in sequence number 403, and may include at least the nucleic acids at positions 106 and 107. Sequence number 403 includes a junction between AGRN and NRG1, and in particular, the junction is between the nucleic acid at position 106 derived from AGRN and the nucleic acid at position 107 derived from NRG1. Preferably, the polynucleotide containing a portion of exon 12 of AGRN fused with a portion of exon 6 of NRG1 has the polynucleotide sequence of SEQ ID NO: 403, or an allele variant thereof.

[0247] In preferred embodiments, a polynucleotide is provided that includes a polynucleotide according to SEQ ID NO: 403, or a polynucleotide comprising about 20, about 30, about 40, or all consecutive nucleic acids from SEQ ID NO: 403, preferably comprising nucleic acids at positions 106 and 107. The number of consecutive nucleic acids may be 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all nucleic acids from SEQ ID NO: 403, preferably comprising nucleic acids at least at positions 106 and 107.

[0248] Preferably, a polynucleotide comprising a portion of exon 6 of NRG1, or a portion of exon 12 of AGRN fused with an allele variant thereof, or an allele variant thereof, further comprises a portion of a longer polynucleotide that comprises or encodes the EGF-like domain of NRG1. Abnormal cells comprising a polynucleotide fusion expressing AGRN or a polypeptide fusion contain or encode the EGF-like domain of NRG1. For rapid detection, diagnosis, or specific purposes, it may be sufficient to indicate that the fusion junction between AGRN and NRG1 is within a frame and occurs at a position that contains the EGF-like domain of NRG1. The EGF-like domain is preferably an EGF-like domain according to SEQ ID NO: 163, or an allele variant thereof having at least 85% identity to SEQ ID NO: 163, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity thereto.

[0249] Preferably, exon 12 of AGRN or a portion of its allele variant is 5' relative to exon 6 of NRG1 or a portion of its allele variant. This orientation at the nucleic acid level results in a fusion polypeptide product containing the N-terminus of AGRN and the C-terminus of NRG1. Furthermore, the AGRN-NRG1 polynucleotide fusion provided herein produces a protein fusion in which the portion from the N-terminus to the fusion junction is a polypeptide sequence from AGRN, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, with the NRG1 portion also providing its EGF-like domain. Thus, the AGRN-NRG1 fusion protein retains the EGF-like domain of NRG1 and retains the ability to promote the growth and survival of human cancers, particularly adenocarcinomas, more specifically subsets of pancreatic ductal adenocarcinoma.

[0250] PVALB-NRG1 polynucleotide fusion The disclosure also provides polynucleotides comprising a PVALB nucleic acid sequence (or a portion of a PVALB nucleic acid sequence) fused with an NRG1 nucleic acid sequence (or a portion of an NRG1 nucleic acid sequence). The fusion also includes allelic variants of the PVALB and NRG1 nucleic acid sequences.

[0251] Preferably, the PVALB nucleic acid sequence or a portion thereof includes or consists of any one of SEQ ID NOs. 439 to 444, or an allele variant of any one of SEQ ID NOs. 439 to 444, and the NRG1 nucleic acid sequence or a portion thereof includes or consists of any one of SEQ ID NOs. 125 to 138, or an allele variant of any one of SEQ ID NOs. 125 to 138. More preferably, the PVALB nucleic acid sequence includes a portion of SEQ ID NO. 444, or an allele variant of SEQ ID NO. 444, and the NRG1 nucleic acid sequence preferably includes a portion of SEQ ID NO. 138, or an allele variant of SEQ ID NO. 138. SEQ ID NOs. 439 to 443 correspond to individual exons 1 to 5 of PVALB according to NM_002854.3, respectively. SEQ ID NO. 444 corresponds to exons 1 to 5 of PVALB according to NM_002854.3. Sequence numbers 125-137 correspond to individual exons 1-13 of the NRG1 sequence following NM_001159999, respectively. Sequence number 138 corresponds to exons 1-13 of NRG1 following NM_001159999.

[0252] In a preferred embodiment, a portion of the PVALB nucleic acid sequence includes 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids derived from any one of sequence numbers 439 to 444, or any allele variant of any one of sequence numbers 439 to 444, and a portion of the NRG1 nucleic acid sequence includes 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids derived from any one of sequence numbers 125 to 138, or any allele variant of any one of sequence numbers 125 to 138.

[0253] A polynucleotide fusion is also provided, comprising a portion of exon 4 of PVALB fused with a portion of exon 6 of NRG1. The exon 4 of PVALB is preferably the exon of SEQ ID NO: 442 or an allele variant of SEQ ID NO: 442, and the exon 6 of NRG1 is preferably the exon of SEQ ID NO: 130 or an allele variant of SEQ ID NO: 130.

[0254] When present in abnormal cells of a patient or subject, the polynucleotide fusion preferably further comprises any sequence 5' from exon 4 of PVALB and any sequence 3' from exon 6 of NRG1, and it may be sufficient to have at least SEQ ID NOs. 442 and 130 present to enable detection of the fusion junction using a polynucleotide-based detection assay. The any sequence 5' from exon 4 of PVALB comprises or consists of one or all of SEQ ID NOs. 439-441 (or any allele variant of SEQ ID NOs. 439-441), and the any sequence 3' from exon 6 of NRG1 comprises or consists of one or all of SEQ ID NOs. 131-137 (or any allele variant of SEQ ID NOs. 131-137).

[0255] Preferably, the allele variant of exon 4 of PVALB has at least 85% identity with SEQ ID NO: 442, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity, and the allele variant of exon 6 of NRG1 has at least 85% identity with SEQ ID NO: 130, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0256] Preferably, a portion of exon 4 of PVALB contains or conforms to SEQ ID NO: 435, and its allele variants have at least 85% identity with respect to SEQ ID NO: 435, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. A portion of exon 6 of NRG1 in the fusion with PVALB is preferably a sequence conforming to or containing SEQ ID NO: 436, and its allele variants have at least 85% identity with respect to SEQ ID NO: 436, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, a portion of exon 4 of PVALB contains or consists of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 435, and contains at least 102 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 435, and may include at least 102 nucleic acids. More preferably, a portion of exon 4 of PVALB includes or follows SEQ ID NO: 435 or its allele variant. Such short polynucleotide sequences are particularly useful for detecting the presence of larger polynucleotide fusions between PVALB and NRG1, and for establishing that such fusions are intraframe oncogenic fusions containing the EGF-like domain of NRG1.

[0257] Alternatively, a portion of exon 4 of PVALB contains or comprises SEQ ID NO: 442 (or an allele variant of SEQ ID NO: 442) and includes at least 110 nucleic acids. Preferably, a portion of exon 4 of PVALB contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 442 or its allele variants, and includes at least 110 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 442, and include at least 110 nucleic acids. In this alternative example, a portion of exon 4 of PVALB more preferably includes or follows SEQ ID NO: 442 or its allele variant. Preferably, a portion of exon 6 of NRG1 in the fusion with PVALB contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 130 or its allele variants, and contains at least one nucleic acid. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 of the nucleic acids in SEQ ID NO: 130, and may include at least the nucleic acid at position 1.

[0258] Preferably, any PVALB-NRG1 polynucleotide fusion provided herein is an intraframe fusion of PVALB and NRG1. More preferably, the fusion is an intraframe fusion comprising exon 4 or a portion of exon 4 of PVALB and exon 6 or a portion of exon 6 of NRG1. The intraframe fusion is preferably the fusion of SEQ ID NO: 437, or an allele variant thereof having at least 85% identity thereto, preferably at least 90%, 92%, 94%, 96%, or 98% identity thereto.

[0259] In alternatively preferred embodiments, the polynucleotide comprising a portion of exon 4 of PVALB fused with a portion of exon 6 of NRG1 comprises 2 to about 10, about 20, about 30, or up to about 40, or all consecutive nucleic acids from SEQ ID NO: 437, including the nucleic acids at positions 102 and 103. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids in sequence number 437, and may include at least the nucleic acids at positions 102 and 103. Sequence number 437 includes a junction between PVALB and NRG1, and in particular, the junction is between the nucleic acid at position 102 derived from PVALB and the nucleic acid at position 103 derived from NRG1. Preferably, the polynucleotide containing a portion of exon 4 of PVALB fused with a portion of exon 6 of NRG1 has the polynucleotide sequence of SEQ ID NO: 437, or an allele variant thereof.

[0260] Preferably, a polynucleotide comprising a portion of exon 6 of NRG1, or a portion of exon 4 of PVALB fused with an allele variant thereof, or an allele variant thereof, further comprises a portion of a longer polynucleotide that comprises or encodes the EGF-like domain of NRG1. Abnormal cells containing PVALB or polynucleotide fusions expressing the polypeptide fusion contain or encode the EGF-like domain of NRG1. For rapid detection, diagnosis, or specific purposes, it may be sufficient to indicate that the fusion junction between PVALB and NRG1 is within a frame and occurs at a position that contains the EGF-like domain of NRG1. The EGF-like domain is preferably an EGF-like domain according to SEQ ID NO: 163, or an allele variant thereof having at least 85% identity to SEQ ID NO: 163, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity thereto.

[0261] Preferably, exon 4 of PVALB or a portion of its allele variant is 5' relative to exon 6 of NRG1 or a portion of its allele variant. This orientation at the nucleic acid level results in a fusion polypeptide product containing the N-terminus of PVALB and the C-terminus of NRG1. Furthermore, the PVALB-NRG1 polynucleotide fusion provided herein produces a protein fusion in which the portion from the N-terminus to the fusion junction is a polypeptide sequence from PVALB, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, with the NRG1 portion also providing its EGF-like domain. Thus, the PVALB-NRG1 fusion protein retains the EGF-like domain of NRG1 and retains the ability to promote the growth and survival of human cancers, particularly adenocarcinomas, more specifically subsets of pancreatic ductal adenocarcinoma.

[0262] APP-NRG1 polynucleotide fusion A polynucleotide fusion is also provided, comprising a portion of exon 14 of APP fused with a portion of exon 6 of NRG1. The exon 14 of APP is preferably the exon of SEQ ID NO: 501 or an allele variant of SEQ ID NO: 501, and the exon 6 of NRG1 is preferably the exon of SEQ ID NO: 130 or an allele variant of SEQ ID NO: 130.

[0263] When present in abnormal cells of a patient or subject, the polynucleotide fusion preferably further comprises any sequence 5' from exon 14 of APP and any sequence 3' from exon 6 of NRG1, and it may be sufficient to have at least SEQ ID NOs. 501 and 130 present to enable detection of the fusion junction using a polynucleotide-based detection assay. The any sequence 5' from exon 14 of APP comprises or consists of one or all of SEQ ID NOs. 488-500 (or any allele variant of SEQ ID NOs. 488-500), and the any sequence 3' from exon 6 of NRG1 comprises or consists of one or all of SEQ ID NOs. 131-137 (or any allele variant of SEQ ID NOs. 131-137).

[0264] Preferably, the allele variant of exon 14 of APP has at least 85% identity with SEQ ID NO: 501, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity, and the allele variant of exon 6 of NRG1 has at least 85% identity with SEQ ID NO: 130, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0265] Preferably, a portion of exon 14 of APP contains or conforms to sequence number 484, and the allele variant has at least 85% identity with respect to sequence number 484, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. A portion of exon 6 of NRG1 in the fusion with APP is preferably a sequence conforming to or containing sequence number 485, and the allele variant has at least 85% identity with respect to sequence number 485, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, a portion of exon 14 of APP contains or consists of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from sequence number 484, and contains at least 54 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 484, and may include at least 54 nucleic acids. More preferably, a portion of exon 14 of APP includes or follows SEQ ID NO: 484 or its allele variant. Such short polynucleotide sequences are particularly useful for detecting the presence of larger polynucleotide fusions between APP and NRG1 and for establishing that such fusions are intraframe oncogenic fusions containing the EGF-like domain of NRG1.

[0266] Alternatively, a portion of exon 14 of APP may contain or consist of SEQ ID NO: 501 (or an allele variant of SEQ ID NO: 501) and include at least 54 nucleic acids. Preferably, a portion of exon 14 of APP may contain or consist of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 501 or its allele variants, and include at least 54 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 501, and include at least 54 nucleic acids. In this alternative example, a portion of exon 14 of APP more preferably includes or follows SEQ ID NO: 501 or its allele variant. Preferably, a portion of exon 6 of NRG1 in the fusion with APP contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 130 or its allele variants, and contains at least one nucleic acid. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 of the nucleic acids in SEQ ID NO: 130, and may include at least the nucleic acid at position 1.

[0267] Preferably, any APP-NRG1 polynucleotide fusion provided herein is an intraframe fusion of APP and NRG1. More preferably, the fusion is an intraframe fusion comprising exon 14 or a portion of exon 14 of APP and exon 6 or a portion of exon 6 of NRG1. The intraframe fusion is preferably the fusion of SEQ ID NO: 486, or an allele variant thereof having at least 85% identity thereto, preferably at least 90%, 92%, 94%, 96%, or 98% identity thereto.

[0268] In alternatively preferred embodiments, the polynucleotide comprising a portion of exon 14 of APP fused with a portion of exon 6 of NRG1 comprises 2 to about 10, about 20, about 30, or up to about 40, or all consecutive nucleic acids from SEQ ID NO: 486, including the nucleic acids at positions 54 and 55. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids in sequence number 486, and may include nucleic acids at least at positions 54 and 55. Sequence number 486 includes a junction between APP and NRG1, and in particular, the junction is between the nucleic acid at position 54 derived from APP and the nucleic acid at position 55 derived from NRG1. Preferably, the polynucleotide containing a portion of exon 14 of APP fused with a portion of exon 6 of NRG1 has the polynucleotide sequence of SEQ ID NO: 486, or an allele variant thereof.

[0269] In preferred embodiments, a polynucleotide is provided that includes a polynucleotide according to SEQ ID NO: 486, or a polynucleotide comprising about 20, about 30, about 40, or all consecutive nucleic acids from SEQ ID NO: 486, preferably comprising nucleic acids at positions 54 and 55. The number of consecutive nucleic acids may be 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all nucleic acids from SEQ ID NO: 486, preferably comprising nucleic acids at least at positions 54 and 55.

[0270] Preferably, a polynucleotide comprising a portion of exon 6 of NRG1, or a portion of exon 14 of APP fused with an allele variant thereof, or an allele variant thereof, further comprises a portion of a longer polynucleotide that comprises or encodes the EGF-like domain of NRG1. Abnormal cells comprising APP or polynucleotide fusions expressing a polypeptide fusion contain or encode the EGF-like domain of NRG1. For rapid detection, diagnosis, or specific purposes, it may be sufficient to indicate that the fusion junction between APP and NRG1 is within a frame and occurs at a position that contains the EGF-like domain of NRG1. The EGF-like domain is preferably an EGF-like domain according to SEQ ID NO: 163, or an allele variant thereof having at least 85% identity to SEQ ID NO: 163, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity thereto.

[0271] Preferably, exon 14 of APP or a portion of its allele variant is 5' relative to exon 6 of NRG1 or a portion of its allele variant. This orientation at the nucleic acid level results in a fusion polypeptide product containing the N-terminus of APP and the C-terminus of NRG1. The APP-NRG1 polynucleotide fusion provided herein also produces a protein fusion, where the portion from the N-terminus to the fusion junction is a polypeptide sequence from APP, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, with the NRG1 portion also providing its EGF-like domain. Thus, the APP-NRG1 fusion protein retains the EGF-like domain of NRG1 and retains the ability to promote the growth and survival of human cancers, particularly adenocarcinomas, more specifically subsets of pancreatic ductal adenocarcinoma.

[0272] WRN-NRG1 polynucleotide fusion A polynucleotide fusion is also provided, comprising a portion of exon 33 of WRN fused with a portion of exon 6 of NRG1. The exon 33 of WRN is preferably the exon of SEQ ID NO: 562 or an allele variant of SEQ ID NO: 562, and the exon 6 of NRG1 is preferably the exon of SEQ ID NO: 130 or an allele variant of SEQ ID NO: 130.

[0273] When present in abnormal cells of a patient or subject, the polynucleotide fusion preferably further comprises any sequence 5' from exon 33 of WRN and any sequence 3' from exon 6 of NRG1, and it may be sufficient to have at least SEQ ID NOs. 562 and 130 to enable detection of the fusion junction using a polynucleotide-based detection assay. The any sequence 5' from exon 33 of WRN comprises or consists of one or all of SEQ ID NOs. 530-561 (or any allele variant of SEQ ID NOs. 530-561), and the any sequence 3' from exon 6 of NRG1 comprises or consists of one or all of SEQ ID NOs. 131-137 (or any allele variant of SEQ ID NOs. 131-137).

[0274] Preferably, the allele variant of exon 33 of WRN has at least 85% identity with SEQ ID NO: 562, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity, and the allele variant of exon 6 of NRG1 has at least 85% identity with SEQ ID NO: 130, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0275] Preferably, a portion of exon 33 of WRN contains or conforms to SEQ ID NO: 526, and its allele variants have at least 85% identity with respect to SEQ ID NO: 526, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. A portion of exon 6 of NRG1 in the fusion with WRN is preferably a sequence conforming to or containing SEQ ID NO: 527, and its allele variants have at least 85% identity with respect to SEQ ID NO: 527, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, a portion of exon 33 of WRN contains or consists of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 526, and contains at least 96 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 526, and include at least 96 nucleic acids. More preferably, a portion of exon 33 of WRN includes or follows SEQ ID NO: 526 or its allele variant. Such short polynucleotide sequences are particularly useful for detecting the presence of larger polynucleotide fusions between WRN and NRG1 and for establishing that such fusions are intraframe oncogenic fusions containing the EGF-like domain of NRG1.

[0276] Alternatively, a portion of exon 33 of the WRN contains or comprises SEQ ID NO: 562 (or an allele variant of SEQ ID NO: 562) and comprises at least 163 nucleic acids. Preferably, a portion of exon 33 of the WRN contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 562 or its allele variants, and comprises at least 163 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 562, and include at least 163 nucleic acids. In this alternative example, a portion of exon 33 of the WRN more preferably includes or follows SEQ ID NO: 562 or its allele variant. Preferably, a portion of exon 6 of NRG1 in the fusion with WRN contains, or comprises, 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 130 or its allele variants, and contains at least one nucleic acid. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 of the nucleic acids in SEQ ID NO: 130, and may include at least the nucleic acid at position 1.

[0277] Preferably, any WRN-NRG1 polynucleotide fusion provided herein is an intraframe fusion of WRN and NRG1. More preferably, the fusion is an intraframe fusion comprising exon 33 or a portion of exon 33 of WRN and exon 6 of NRG1 or a portion of exon 6 of NRG1. The intraframe fusion is preferably the fusion of SEQ ID NO: 528, or an allele variant thereof having at least 85% identity thereto, preferably at least 90%, 92%, 94%, 96%, or 98% identity thereto.

[0278] In alternatively preferred embodiments, the polynucleotide comprising a portion of exon 33 of WRN fused with a portion of exon 6 of NRG1 comprises 2 to about 10, about 20, about 30, or up to about 40, or all consecutive nucleic acids from SEQ ID NO: 528, including nucleic acids at positions 96 and 97. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids in sequence number 528, and may include nucleic acids at least at positions 96 and 97. Sequence number 528 includes a junction between WRN and NRG1, and in particular, the junction is between the nucleic acid at position 96 derived from WRN and the nucleic acid at position 97 derived from NRG1. Preferably, the polynucleotide containing a portion of exon 33 of WRN fused with a portion of exon 6 of NRG1 has the polynucleotide sequence of SEQ ID NO: 528, or an allele variant thereof.

[0279] In a preferred embodiment, there is provided a polynucleotide comprising the polynucleotide according to SEQ ID NO: 528, or about 20, about 30, about 40, or all of the consecutive nucleic acids from SEQ ID NO: 528, preferably comprising the nucleic acids at positions 96 and 97. The number of consecutive nucleic acids may be 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 528, preferably comprising nucleic acids at least at positions 96 and 97.

[0280] Preferably, a polynucleotide comprising a portion of exon 6 of NRG1, or a portion of exon 33 of WRN fused to its allelic variant, or its allelic variant further comprises the EGF-like domain of NRG1 or is part of a longer polynucleotide encoding the same. An abnormal cell comprising a polynucleotide fusion comprising WRN or expressing a polypeptide fusion encodes or comprises the EGF-like domain of NRG1. For purposes of rapid detection, diagnosis or identification, it may be sufficient to show that the fusion junction between WRN and NRG1 is in-frame and occurs at a position such that the resulting fusion product, nucleic acid or protein comprises the EGF-like domain of NRG1. The EGF-like domain is preferably the EGF-like domain according to SEQ ID NO: 163, or an allelic variant thereof having at least 85% identity to SEQ ID NO: 163, preferably at least 90% identity thereto, 92%, 94%, 96%, or more preferably at least 98% sequence identity thereto.

[0281] Preferably, exon 33 of WRN or a portion of its allelic variant is 5' relative to exon 6 of NRG1 or a portion of its allelic variant. This orientation at the nucleic acid level results in a fusion polypeptide product containing the N-terminus of WRN and the C-terminus of NRG1. Also, the WRN-NRG1 polynucleotide fusions provided herein produce a protein fusion, wherein the portion from the N-terminus to the fusion junction is a polypeptide sequence from WRN and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, and the NRG1 portion also provides its EGF-like domain. Thus, the WRN-NRG1 fusion protein retains the EGF-like domain of NRG1 and retains the ability to promote the growth and survival of a subset of human cancers, particularly breast cancer.

[0282] DAAM1-NRG1 polynucleotide fusion According to the present disclosure, there is also provided a polynucleotide comprising a DAAM1 nucleic acid sequence (or a portion of the DAAM1 nucleic acid sequence) fused to an NRG1 nucleic acid sequence (or a portion of the NRG1 nucleic acid sequence). The fusions also include allelic variants of the DAAM1 and NRG1 nucleic acid sequences.

[0283] Preferably, the DAAM1 nucleic acid sequence or a portion thereof includes or consists of any one of sequence numbers 606 to 631, or an allele variant of any one of sequence numbers 606 to 631, and the NRG1 nucleic acid sequence or a portion thereof includes or consists of any one of sequence numbers 125 to 138, or an allele variant of any one of sequence numbers 125 to 138. More preferably, the DAAM1 nucleic acid sequence includes a portion of sequence number 631, or an allele variant of sequence number 631, and the NRG1 nucleic acid sequence includes a portion of sequence number 138, or an allele variant of sequence number 138. Sequence numbers 606 to 630 each correspond to individual exons 1 to 25 of DAAM1 according to NM_001270520.2. Sequence number 631 corresponds to exons 1 to 25 of DAAM1 according to NM_001270520.2. Sequence numbers 125-137 correspond to individual exons 1-13 of the NRG1 sequence according to NM_001159999.3, respectively. Sequence number 138 corresponds to exons 1-13 of NRG1 according to NM_001159999.3.

[0284] In a preferred embodiment, a portion of the DAAM1 nucleic acid sequence includes 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids derived from any one of sequence numbers 606 to 631, or an allele variant of any one of sequence numbers 606 to 631, and a portion of the NRG1 nucleic acid sequence includes 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids derived from any one of sequence numbers 125 to 138, or an allele variant of any one of sequence numbers 125 to 138.

[0285] Preferably, the allele variant of the DAAM1 nucleic acid sequence has at least 85% identity with any one of sequence numbers 606 to 631, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity with respect to it, and the allele variant of the NRG1 nucleic acid sequence has at least 85% identity with any one of sequence numbers 125 to 138, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity with respect to it.

[0286] Preferably, the DAAM1 nucleic acid sequence or a portion thereof is 5' relative to the NRG1 nucleic acid sequence or a portion thereof.

[0287] Preferably, a polynucleotide containing the DAAM1 nucleic acid sequence or a portion of the sequence of DAAM1 fused with the NRG1 nucleic acid sequence or a portion of the sequence contains or encodes the EGF-like domain of NRG1. Abnormal cells containing a DAAM1-NRG1 polynucleotide fusion contain or encode the EGF-like domain of NRG1. For detection, diagnosis, or specific purposes, it may be sufficient to indicate that the fusion junction between DAAM1 and NRG1 is within a frame and that the resulting fusion nucleic acid occurs at a position that encodes the EGF-like domain of NRG1. The EGF-like domain is preferably an EGF-like domain according to SEQ ID NO: 163, or an allele variant thereof having at least 85% identity with respect to SEQ ID NO: 163, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0288] A polynucleotide fusion is also provided, comprising a portion of exon 1 of DAAM1 fused with a portion of exon 1 of NRG1. The exon 1 of DAAM1 is preferably the exon of SEQ ID NO: 606 or an allele variant of SEQ ID NO: 606, and the exon 1 of NRG1 is preferably the exon of SEQ ID NO: 125 or an allele variant of SEQ ID NO: 125.

[0289] When present in abnormal cells of a patient or subject, the polynucleotide fusion preferably further comprises any sequence 5' from exon 1 of DAAM1 and any sequence 3' from exon 1 of NRG1, and it may be sufficient to have at least SEQ ID NOs. 606 and 125 present to enable detection of the fusion junction using a polynucleotide-based detection assay. The any sequence 5' from exon 1 of DAAM1 comprises or consists of SEQ ID NOs. 606 (or any allele variant of SEQ ID NOs. 606), and the any sequence 3' from exon 1 of NRG1 comprises or consists of one or all of SEQ ID NOs. 126-137 (or any allele variants of SEQ ID NOs. 126-137).

[0290] Preferably, the allele variant of exon 1 of DAAM1 has at least 85% identity with SEQ ID NO: 606, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity, and the allele variant of exon 1 of NRG1 has at least 85% identity with SEQ ID NO: 125, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0291] Preferably, a portion of exon 1 of DAAM1 contains or conforms to sequence number 603, and its allele variants have at least 85% identity with respect to sequence number 603, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. A portion of exon 1 of NRG1 in a fusion with DAAM1 is preferably a sequence conforming to or containing sequence number 604, and its allele variants have at least 85% identity with respect to sequence number 604, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, a portion of exon 1 of DAAM1 contains or consists of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from sequence number 603, and contains at least the nucleic acid at position 75. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 603, and may include at least 75 nucleic acids. More preferably, a portion of exon 1 of DAAM1 includes or follows SEQ ID NO: 603 or its allele variant. Such short polynucleotide sequences are particularly useful for detecting the presence of larger polynucleotide fusions between DAAM1 and NRG1, and for establishing that such fusions are intraframe oncogenic fusions containing the EGF-like domain of NRG1.

[0292] Alternatively, a portion of exon 1 of DAAM1 contains or comprises SEQ ID NO: 606 (or an allele variant of SEQ ID NO: 606) and comprises at least 102 nucleic acids. Preferably, a portion of exon 1 of DAAM1 contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 606 or its allele variants, and comprises at least 102 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 606, and may include at least 102 nucleic acids. In this alternative example, a portion of exon 1 of DAAM1 more preferably includes or follows SEQ ID NO: 606 or its allele variant. Preferably, in the fusion with DAAM1, a portion of exon 1 of NRG1 contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 125 or its allele variant, and contains at least the nucleic acid at position 1. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 of the nucleic acids in SEQ ID NO: 125, and may include at least the nucleic acid at position 1.

[0293] In alternatively preferred embodiments, the polynucleotide comprising a portion of exon 1 of DAAM1 fused with a portion of exon 1 of NRG1 comprises 2 to about 10, about 20, about 30, or up to about 40, or all consecutive nucleic acids from SEQ ID NO: 605, including the nucleic acids at positions 75 and 76. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids in Sequence ID No. 605, and includes nucleic acids at least at positions 75 and 76. Sequence ID No. 605 includes a junction between DAAM1 and NRG1, and in particular, the junction is between the nucleic acid at position 75 derived from DAAM1 and the nucleic acid at position 76 derived from NRG1. Preferably, the polynucleotide containing a portion of exon 1 of DAAM1 fused with a portion of exon 1 of NRG1 has the polynucleotide sequence of SEQ ID NO: 605, or an allele variant thereof.

[0294] Preferably, any DAAM1-NRG1 polynucleotide fusion provided herein is a fusion of a portion of the untranslated region of DAAM1 and a portion of the untranslated region of NRG1. More preferably, the fusion comprises exon 1 or a portion of exon 1 of DAAM1 and exon 1 or a portion of exon 1 of NRG1. The fusion is preferably the fusion of SEQ ID NO: 605, or an allele variant thereof having at least 85% identity thereto, preferably at least 90%, 92%, 94%, 96%, or 98% identity thereto.

[0295] Preferably, a portion of exon 1 of DAAM1 or its allele variant is 5' relative to a portion of exon 1 of NRG1 or its allele variant. Therefore, the NRG1 protein is expected to be located downstream of the DAAM1 promoter and transcribed by the promoter. Thus, the resulting fusion results in the expression of a non-protein fusion NRG1 protein, and therefore contains an EGF-like domain, thereby promoting the growth and survival of human cancers, specifically a subset of breast cancer.

[0296] ASPH-NRG1 polynucleotide fusion The disclosure also provides polynucleotides comprising an ASPH nucleic acid sequence (or a portion of an ASPH nucleic acid sequence) fused with an NRG1 nucleic acid sequence (or a portion of an NRG1 nucleic acid sequence). The fusion also includes allelic variants of the ASPH and NRG1 nucleic acid sequences.

[0297] Preferably, the ASPH nucleic acid sequence or a portion thereof includes or consists of any one of SEQ ID NOs. 637 to 662, or an allele variant of any one of SEQ ID NOs. 637 to 662, and the NRG1 nucleic acid sequence or a portion thereof includes or consists of any one of SEQ ID NOs. 125 to 138, or an allele variant of any one of SEQ ID NOs. 125 to 138. More preferably, the ASPH nucleic acid sequence includes a portion of SEQ ID NOs. 662, or an allele variant of SEQ ID NOs. 661, each corresponds to individual exons 1 to 25 of ASPH according to NM_001164750.2. SEQ ID NOs. 662 corresponds to exons 1 to 25 of ASPH according to NM_001164750.2. Sequence numbers 125-137 correspond to individual exons 1-13 of the NRG1 sequence according to NM_001159999.3, respectively. Sequence number 138 corresponds to exons 1-13 of NRG1 according to NM_001159999.3.

[0298] In a preferred embodiment, a portion of the ASPH nucleic acid sequence includes 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids derived from any one of SEQ ID NOs. 637-662, or an allele variant of any one of SEQ ID NOs. 637-662, and a portion of the NRG1 nucleic acid sequence includes 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids derived from any one of SEQ ID NOs. 125-138, or an allele variant of any one of SEQ ID NOs. 125-138.

[0299] Preferably, the allele variant of the ASPH nucleic acid sequence has at least 85% identity with any one of sequence numbers 637 to 662, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity with respect to it, and the allele variant of the NRG1 nucleic acid sequence has at least 85% identity with any one of sequence numbers 125 to 138, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity with respect to it.

[0300] Preferably, the ASPH nucleic acid sequence or a portion thereof is 5' relative to the NRG1 nucleic acid sequence or a portion thereof.

[0301] Preferably, a polynucleotide containing the ASPH nucleic acid sequence or a portion of the sequence of ASPH fused with the NRG1 nucleic acid sequence or a portion of the sequence contains or encodes the EGF-like domain of NRG1. Abnormal cells containing or expressing the ASPH-NRG1 polynucleotide fusion contain or encode the EGF-like domain of NRG1. For detection, diagnosis, or specific purposes, it may be sufficient to indicate that the fusion junction between ASPH and NRG1 is within a frame and occurs at a position that contains the EGF-like domain of NRG1. The EGF-like domain is preferably an EGF-like domain according to SEQ ID NO: 163, or an allele variant thereof having at least 85% identity to SEQ ID NO: 163, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity thereto.

[0302] A polynucleotide fusion is also provided, comprising a portion of exon 22 of ASPH fused with a portion of exon 2 of NRG1. The exon 22 of ASPH is preferably the exon of SEQ ID NO: 658 or an allele variant of SEQ ID NO: 658, and the exon 2 of NRG1 is preferably the exon of SEQ ID NO: 126 or an allele variant of SEQ ID NO: 126.

[0303] When present in abnormal cells of a patient or subject, the polynucleotide fusion preferably further comprises any sequence 5' from exon 22 of ASPH and any sequence 3' from exon 2 of NRG1, and it may be sufficient to have at least SEQ ID NOs. 658 and 126 present to enable detection of the fusion junction using a polynucleotide-based detection assay. The any sequence 5' from exon 22 of ASPH comprises or consists of one or all of SEQ ID NOs. 637-657 (or any allele variant of SEQ ID NOs. 637-657), and the any sequence 3' from exon 2 of NRG1 comprises or consists of one or all of SEQ ID NOs. 127-137 (or any allele variant of SEQ ID NOs. 127-137).

[0304] Preferably, the allelic variant of exon 22 of ASPH has at least 85% identity, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity to SEQ ID NO: 658, and the allelic variant of exon 2 of NRG1 has at least 85% identity, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity to SEQ ID NO: 126.

[0305] Preferably, a portion of exon 22 of ASPH contains or conforms to SEQ ID NO: 633, and its allele variants have at least 85% identity with respect to SEQ ID NO: 633, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. A portion of exon 2 of NRG1 in the fusion with ASPH is preferably a sequence conforming to or containing SEQ ID NO: 634, and its allele variants have at least 85% identity with respect to SEQ ID NO: 634, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, a portion of exon 22 of ASPH contains or consists of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 633, and contains at least the nucleic acid at position 75. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 633, and include at least 75 nucleic acids. More preferably, a portion of exon 22 of ASPH includes or follows SEQ ID NO: 633 or its allele variant. Such short polynucleotide sequences are particularly useful for detecting the presence of larger polynucleotide fusions between ASPH and NRG1 and for establishing that such fusions are intraframe oncogenic fusions containing the EGF-like domain of NRG1.

[0306] Alternatively, a portion of exon 22 of ASPH may contain or consist of SEQ ID NO: 658 (or an allele variant of SEQ ID NO: 658) and include at least 136 nucleic acids. Preferably, a portion of exon 22 of ASPH may contain or consist of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 658 or its allele variants, and include at least 136 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 658, and include at least 136 nucleic acids. In this alternative example, a portion of exon 22 of ASPH more preferably includes or follows SEQ ID NO: 658 or its allele variant. Preferably, a portion of exon 2 of NRG1 in the fusion with ASPH contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 126 or its allele variant, and contains at least one nucleic acid. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 of the nucleic acids in SEQ ID NO: 126, and may include at least the nucleic acid at position 1.

[0307] In alternatively preferred embodiments, the polynucleotide comprising a portion of exon 22 of ASPH fused with a portion of exon 2 of NRG1 comprises 2 to about 10, about 20, about 30, or up to about 40, or all consecutive nucleic acids from SEQ ID NO: 635, including the nucleic acids at positions 75 and 76. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids in sequence number 635, and may include nucleic acids at least at positions 75 and 76. Sequence number 635 includes a junction between ASPH and NRG1, and in particular, the junction is between the nucleic acid at position 75 derived from ASPH and the nucleic acid at position 76 derived from NRG1. Preferably, the polynucleotide containing a portion of exon 22 of ASPH fused with a portion of exon 2 of NRG1 has the polynucleotide sequence of SEQ ID NO: 635, or an allele variant thereof.

[0308] Preferably, any ASPH-NRG1 polynucleotide fusion provided herein is an intraframe fusion of ASPH and NRG1. More preferably, the fusion is an intraframe fusion comprising exon 22 or a portion of exon 22 of ASPH and exon 2 of NRG1 or a portion of exon 2 of NRG1. The intraframe fusion is preferably the fusion of SEQ ID NO: 635, or an allele variant thereof having at least 85% identity thereto, preferably at least 90%, 92%, 94%, 96%, or 98% identity thereto.

[0309] Preferably, exon 22 of ASPH or a portion of its allele variant is 5' relative to exon 2 of NRG1 or a portion of its allele variant. This orientation at the nucleic acid level results in a fusion polypeptide product containing the N-terminus of ASPH and the C-terminus of NRG1. Furthermore, the ASPH-NRG1 polynucleotide fusion provided herein produces a protein fusion in which the portion from the N-terminus to the fusion junction is a polypeptide sequence from ASPH, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, with the NRG1 portion also providing its EGF-like domain. Thus, the ASPH-NRG1 fusion protein retains the EGF-like domain of NRG1 and retains the ability to promote the growth and survival of human cancers, particularly adenocarcinomas, more specifically subsets of colorectal adenocarcinoma.

[0310] NOTCH2-NRG1 polynucleotide fusion A polynucleotide fusion is also provided, comprising a portion of exon 6 of NOTCH2 fused with a portion of exon 6 of NRG1. The exon 6 of NOTCH2 is preferably the exon of SEQ ID NO: 700 or an allele variant of SEQ ID NO: 700, and the exon 6 of NRG1 is preferably the exon of SEQ ID NO: 130 or an allele variant of SEQ ID NO: 130.

[0311] When present in abnormal cells of a patient or subject, the polynucleotide fusion preferably further comprises any sequence 5' from exon 6 of NOTCH2 and any sequence 3' from exon 6 of NRG1, and it may be sufficient to have at least SEQ ID NOs. 700 and 130 to enable detection of the fusion junction using a polynucleotide-based detection assay. Any sequence 5' from exon 6 of NOTCH2 comprises or consists of one or all of SEQ ID NOs. 695-699 (or any allele variant of SEQ ID NOs. 695-699), and any sequence 3' from exon 6 of NRG1 comprises or consists of one or all of SEQ ID NOs. 131-137 (or any allele variant of SEQ ID NOs. 131-137).

[0312] Preferably, the allele variant of exon 6 of NOTCH2 has at least 85% identity with SEQ ID NO: 700, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity, and the allele variant of exon 6 of NRG1 has at least 85% identity with SEQ ID NO: 130, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0313] Preferably, a portion of exon 6 of NOTCH2 contains or conforms to sequence number 691, and its allele variants have at least 85% identity with respect to sequence number 691, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. A portion of exon 6 of NRG1 in a fusion with NOTCH2 is preferably a sequence conforming to or containing sequence number 692, and its allele variants have at least 85% identity with respect to sequence number 692, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, a portion of exon 6 of NOTCH2 contains or consists of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from sequence number 691, and contains at least the nucleic acid at position 75. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 691, and include at least 75 nucleic acids. More preferably, a portion of exon 6 of NOTCH2 includes or follows SEQ ID NO: 691 or its allele variant. Such short polynucleotide sequences are particularly useful for detecting the presence of larger polynucleotide fusions between NOTCH2 and NRG1, and for establishing that such fusions are intraframe oncogenic fusions containing the EGF-like domain of NRG1.

[0314] Alternatively, a portion of exon 6 of NOTCH2 contains or comprises SEQ ID NO: 700 (or an allele variant of SEQ ID NO: 700) and comprises at least 234 nucleic acids. Preferably, a portion of exon 6 of NOTCH2 contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 700 or its allele variants, and comprises at least 234 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids, and may include at least 234 nucleic acids. In this alternative example, a portion of exon 6 of NOTCH2 more preferably includes or follows sequence number 700 or its allele variant. Preferably, a portion of exon 6 of NRG1 in the fusion with NOTCH2 contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 130 or its allele variants, and contains at least one nucleic acid. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 of the nucleic acids in SEQ ID NO: 130, and may include at least the nucleic acid at position 1.

[0315] Preferably, any NOTCH2-NRG1 polynucleotide fusion provided herein is an intraframe fusion of NOTCH2 and NRG1. More preferably, the fusion is an intraframe fusion comprising exon 6 or a portion of exon 6 of NOTCH2 and exon 6 or a portion of exon 6 of NRG1. The intraframe fusion is preferably the fusion of SEQ ID NO: 693, or an allele variant thereof having at least 85% identity thereto, preferably at least 90%, 92%, 94%, 96%, or 98% identity thereto.

[0316] In alternatively preferred embodiments, the polynucleotide comprising a portion of exon 6 of NOTCH2 fused with a portion of exon 6 of NRG1 comprises 2 to about 10, about 20, about 30, or up to about 40, or all consecutive nucleic acids from SEQ ID NO: 693, including the nucleic acids at positions 75 and 76. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids in sequence number 693, and may include nucleic acids at least at positions 75 and 76. Sequence number 693 includes a junction between NOTCH2 and NRG1, and in particular, the junction is between the nucleic acid at position 75 derived from NOTCH2 and the nucleic acid at position 76 derived from NRG1. Preferably, the polynucleotide containing a portion of exon 6 of NOTCH2 fused with a portion of exon 6 of NRG1 has the polynucleotide sequence of SEQ ID NO: 693, or an allele variant thereof.

[0317] In preferred embodiments, a polynucleotide is provided that includes a polynucleotide according to SEQ ID NO: 693, or a polynucleotide comprising about 20, about 30, about 40, or all consecutive nucleic acids from SEQ ID NO: 693, preferably comprising nucleic acids at positions 75 and 76. The number of consecutive nucleic acids may be 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all nucleic acids from SEQ ID NO: 693, preferably comprising nucleic acids at least at positions 75 and 76.

[0318] Preferably, a polynucleotide containing a portion of exon 6 of NOTCH2, or a portion of exon 6 of NRG1 fused with an allele variant thereof, or an allele variant thereof, further contains or encodes the EGF-like domain of NRG1. Abnormal cells containing NOTCH2, or polynucleotide fusions expressing the polypeptide fusion, contain or encode the EGF-like domain of NRG1. For rapid detection, diagnosis, or specific purposes, it may be sufficient to indicate that the fusion junction between NOTCH2 and NRG1 is within a frame and occurs at a position that contains the EGF-like domain of NRG1. The EGF-like domain is preferably the EGF-like domain according to SEQ ID NO: 163, or an allele variant thereof having at least 85% identity to SEQ ID NO: 163, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity thereto.

[0319] Preferably, a portion of exon 6 of NOTCH2 or its allele variant is 5' relative to exon 6 of NRG1 or its allele variant. This orientation at the nucleic acid level results in a fusion polypeptide product containing the N-terminus of NOTCH2 and the C-terminus of NRG1. Furthermore, the NOTCH2-NRG1 polynucleotide fusion provided herein produces a protein fusion in which the portion from the N-terminus to the fusion junction is a polypeptide sequence from NOTCH2, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, with the NRG1 portion also providing its EGF-like domain. Thus, the NOTCH2-NRG1 fusion protein retains the EGF-like domain of NRG1 and retains the ability to promote the growth and survival of human cancers, particularly adenocarcinomas, more specifically subsets of pancreatic ductal adenocarcinoma.

[0320] CD74-NRG1 polynucleotide fusion A polynucleotide fusion is also provided, comprising a portion of CD74 exon 2 fused with a portion of NRG1 exon 2. The CD74 exon 2 is preferably the exon of SEQ ID NO: 720 or an allele variant of SEQ ID NO: 720, and the NRG1 exon 2 is preferably the exon of SEQ ID NO: 126 or an allele variant of SEQ ID NO: 126.

[0321] When present in abnormal cells of a patient or subject, the polynucleotide fusion preferably further comprises any sequence 5' from exon 2 of CD74 and any sequence 3' from exon 2 of NRG1, and it may be sufficient to have at least SEQ ID NOs. 720 and 126 present to enable detection of the fusion junction using a polynucleotide-based detection assay. The any sequence 5' from exon 2 of CD74 comprises or consists of SEQ ID NOs. 719 (or any allele variant of SEQ ID NOs. 719), and the any sequence 3' from exon 2 of NRG1 comprises or consists of one or all of SEQ ID NOs. 127-137 (or any allele variant of SEQ ID NOs. 127-137).

[0322] Preferably, the allele variant of exon 2 of CD74 has at least 85% identity with SEQ ID NO: 720, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity, and the allele variant of exon 2 of NRG1 has at least 85% identity with SEQ ID NO: 126, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0323] Preferably, a portion of exon 2 of CD74 contains or conforms to sequence number 715, and its allele variants have at least 85% identity with respect to sequence number 715, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. A portion of exon 2 of NRG1 in a fusion with CD74 is preferably a sequence conforming to or containing sequence number 716, and its allele variants have at least 85% identity with respect to sequence number 716, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, a portion of exon 2 of CD74 contains or consists of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from sequence number 715, and contains at least the nucleic acid at position 75. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids, and may include at least 75 nucleic acids. More preferably, a portion of exon 2 of CD74 includes or follows sequence number 715 or its allele variant. Such short polynucleotide sequences are particularly useful for detecting the presence of larger polynucleotide fusions between CD74 and NRG1, and for establishing that such fusions are intraframe oncogenic fusions containing the EGF-like domain of NRG1.

[0324] Alternatively, a portion of exon 2 of CD74 contains or comprises SEQ ID NO: 720 (or an allele variant of SEQ ID NO: 720) and comprises at least 173 nucleic acids. Preferably, a portion of exon 2 of CD74 contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 720 or its allele variants, and comprises at least 173 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids, and may include at least 173 nucleic acids. In this alternative example, a portion of exon 2 of CD74 more preferably includes or follows sequence number 720 or its allele variant. Preferably, the portion of exon 2 of NRG1 in the fusion with CD74 contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 126 or its allele variant, and contains at least one nucleic acid. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 of the nucleic acids in SEQ ID NO: 126, and may include at least the nucleic acid at position 1.

[0325] Preferably, any CD74-NRG1 polynucleotide fusion provided herein is an intraframe fusion of CD74 and NRG1. More preferably, the fusion is an intraframe fusion comprising exon 2 or a portion of exon 2 of CD74 and exon 2 or a portion of exon 2 of NRG1. The intraframe fusion is preferably the fusion of SEQ ID NO: 717, or an allele variant thereof having at least 85% identity thereto, preferably at least 90%, 92%, 94%, 96%, or 98% identity thereto.

[0326] In alternatively preferred embodiments, the polynucleotide comprising a portion of exon 2 of CD74 fused with a portion of exon 2 of NRG1 comprises 2 to about 10, about 20, about 30, or up to about 40, or all consecutive nucleic acids from SEQ ID NO: 717, including nucleic acids at positions 75 and 76. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids in sequence number 717, and may include nucleic acids at least at positions 75 and 76. Sequence number 717 includes a junction between CD74 and NRG1, and in particular, the junction is between the nucleic acid at position 75 derived from CD74 and the nucleic acid at position 76 derived from NRG1. Preferably, the polynucleotide containing a portion of exon 2 of CD74 fused with a portion of exon 2 of NRG1 has the polynucleotide sequence of SEQ ID NO: 717, or an allele variant thereof.

[0327] In preferred embodiments, a polynucleotide is provided that comprises a polynucleotide according to SEQ ID NO: 717, or a polynucleotide comprising about 20, about 30, about 40, or all consecutive nucleic acids from SEQ ID NO: 717, preferably comprising nucleic acids at positions 75 and 76. The number of consecutive nucleic acids may be 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all nucleic acids from SEQ ID NO: 717, preferably comprising nucleic acids at least at positions 75 and 76.

[0328] Preferably, a polynucleotide comprising a portion of exon 2 of NRG1, or a portion of exon 2 of CD74 fused with an allele variant thereof, or an allele variant thereof, further comprises a portion of a longer polynucleotide that comprises or encodes the EGF-like domain of NRG1. Abnormal cells comprising CD74 or polynucleotide fusions expressing a polypeptide fusion contain or encode the EGF-like domain of NRG1. For rapid detection, diagnosis, or specific purposes, it may be sufficient to indicate that the fusion junction between CD74 and NRG1 is within a frame and occurs at a position that contains the EGF-like domain of NRG1. The EGF-like domain is preferably an EGF-like domain according to SEQ ID NO: 163, or an allele variant thereof having at least 85% identity to SEQ ID NO: 163, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity thereto.

[0329] Preferably, a portion of exon 2 of CD74 or its allele variant is 5' relative to exon 2 of NRG1 or its allele variant. This orientation at the nucleic acid level results in a fusion polypeptide product containing the N-terminus of CD74 and the C-terminus of NRG1. The CD74-NRG1 polynucleotide fusion provided herein also produces a protein fusion, where the portion from the N-terminus to the fusion junction is a polypeptide sequence from CD74, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, with the NRG1 portion also providing its EGF-like domain. Thus, the CD74-NRG1 fusion protein retains the EGF-like domain of NRG1 and retains the ability to promote the growth and survival of human cancers, particularly a subset of lung cancer.

[0330] SDC4-NRG1 polynucleotide fusion A polynucleotide fusion is also provided, comprising a portion of exon 2 of SDC4 fused with a portion of exon 2 of NRG1. The exon 2 of SDC4 is preferably the exon of SEQ ID NO: 746 or an allele variant of SEQ ID NO: 746, and the exon 2 of NRG1 is preferably the exon of SEQ ID NO: 126 or an allele variant of SEQ ID NO: 126.

[0331] Preferably, the allele variant of exon 2 of SDC4 has at least 85% identity with SEQ ID NO: 746, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity, and the allele variant of exon 2 of NRG1 has at least 85% identity with SEQ ID NO: 126, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0332] Preferably, a portion of exon 2 of SDC4 contains or conforms to sequence number 741, and its allele variants have at least 85% identity with respect to sequence number 741, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. A portion of exon 2 of NRG1 in a fusion with SDC4 is preferably a sequence conforming to or containing sequence number 742, and its allele variants have at least 85% identity with respect to sequence number 742, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, a portion of exon 2 of SDC4 contains or consists of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from sequence number 741, and contains at least the nucleic acid at position 75. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 741, and include at least 75 nucleic acids. More preferably, a portion of exon 2 of the SDC4 includes or follows SEQ ID NO: 741 or its allele variant. Such short polynucleotide sequences are particularly useful for detecting the presence of a larger polynucleotide fusion between SDC4 and NRG1, and for establishing that such a fusion is an intraframe oncogenic fusion containing the EGF-like domain of NRG1.

[0333] Alternatively, a portion of exon 2 of SDC4 contains or comprises SEQ ID NO: 746 (or an allele variant of SEQ ID NO: 746) and comprises at least 139 nucleic acids. Preferably, a portion of exon 2 of SDC4 contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 746 or its allele variants, and comprises at least 139 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 746, and include at least 139 nucleic acids. In this alternative example, a portion of exon 2 of SDC4 more preferably includes or follows SEQ ID NO: 746 or its allele variant. Preferably, the portion of exon 2 of NRG1 in the fusion with SDC4 contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 126 or its allele variants, and contains at least one nucleic acid. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 of the nucleic acids in SEQ ID NO: 126, and may include at least the nucleic acid at position 1.

[0334] Preferably, any SDC4-NRG1 polynucleotide fusion provided herein is an intraframe fusion of SDC4 and NRG1. More preferably, the fusion is an intraframe fusion comprising exon 2 or a portion of exon 2 of SDC4 and exon 2 or a portion of exon 2 of NRG1. The intraframe fusion is preferably the fusion of SEQ ID NO: 743, or an allele variant thereof having at least 85% identity thereto, preferably at least 90%, 92%, 94%, 96%, or 98% identity thereto.

[0335] In alternatively preferred embodiments, the polynucleotide comprising the portion of exon 2 of SDC4 fused with the portion of exon 2 of NRG1 comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 743, including the nucleic acids at positions 75 and 76. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids in sequence number 743, and may include nucleic acids at least at positions 75 and 76. Sequence number 743 includes a junction between SDC4 and NRG1, and in particular, the junction is between the nucleic acid at position 75 derived from SDC4 and the nucleic acid at position 76 derived from NRG1. Preferably, the polynucleotide containing a portion of exon 2 of SDC4 fused with a portion of exon 2 of NRG1 has the polynucleotide sequence of SEQ ID NO: 743, or an allele variant thereof.

[0336] In preferred embodiments, a polynucleotide is provided that comprises a polynucleotide according to SEQ ID NO: 743, or a polynucleotide comprising about 20, about 30, about 40, or all consecutive nucleic acids from SEQ ID NO: 743, preferably comprising nucleic acids at positions 75 and 76. The number of consecutive nucleic acids may be 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all nucleic acids from SEQ ID NO: 743, preferably comprising nucleic acids at least at positions 75 and 76.

[0337] Preferably, a polynucleotide comprising a portion of exon 2 of NRG1, or a portion of exon 2 of SDC4 fused with an allele variant thereof, or an allele variant thereof, further comprises a portion of a longer polynucleotide that comprises or encodes the EGF-like domain of NRG1. Abnormal cells comprising the SDC4 or a polynucleotide fusion expressing the polypeptide fusion contain or encode the EGF-like domain of NRG1. For rapid detection, diagnosis, or specific purposes, it may be sufficient to indicate that the fusion junction between SDC4 and NRG1 is within a frame and occurs at a position that contains the EGF-like domain of NRG1. The EGF-like domain is preferably an EGF-like domain according to SEQ ID NO: 163, or an allele variant thereof having at least 85% identity to SEQ ID NO: 163, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity thereto.

[0338] Preferably, a portion of exon 2 of SDC4 or its allele variant is 5' relative to a portion of exon 2 of NRG1 or its allele variant. This orientation at the nucleic acid level results in a fusion polypeptide product containing the N-terminus of SDC4 and the C-terminus of NRG1. The SDC4-NRG1 polynucleotide fusion provided herein also produces a protein fusion, where the portion from the N-terminus to the fusion junction is a polypeptide sequence from SDC4, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, with the NRG1 portion also providing its EGF-like domain. Thus, the SDC4-NRG1 fusion protein retains the EGF-like domain of NRG1 and retains the ability to promote the growth and survival of human cancers, particularly a subset of lung cancer.

[0339] When present in abnormal cells of a patient or subject, the polynucleotide fusion preferably further comprises any sequence 5' from exon 2 of SDC4 and any sequence 3' from exon 2 of NRG1, and it may be sufficient to have at least SEQ ID NOs. 746 and 126 present to enable detection of the fusion junction using a polynucleotide-based detection assay. Any sequence 5' from exon 2 of SDC4 comprises or consists of SEQ ID NOs. 745 (or any allele variant of SEQ ID NOs. 745), and any sequence 3' from exon 2 of NRG1 comprises or consists of one or all of SEQ ID NOs. 127-137 (or any allele variant of SEQ ID NOs. 127-137).

[0340] Furthermore, a polynucleotide fusion is provided that includes a portion of exon 4 of SDC4 fused with a portion of exon 2 of NRG1. The exon 4 of SDC4 is preferably the exon of SEQ ID NO: 748 or an allele variant of SEQ ID NO: 748, and the exon 2 of NRG1 is preferably the exon of SEQ ID NO: 126 or an allele variant of SEQ ID NO: 126.

[0341] Preferably, the allele variant of exon 4 of SDC4 has at least 85% identity with SEQ ID NO: 748, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity, and the allele variant of exon 2 of NRG1 has at least 85% identity with SEQ ID NO: 126, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0342] Preferably, a portion of exon 4 of SDC4 contains or conforms to sequence number 822, and its allele variants have at least 85% identity with respect to sequence number 822, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. A portion of exon 2 of NRG1 in the fusion with SDC4 is preferably a sequence conforming to or containing sequence number 823, and its allele variants have at least 85% identity with respect to sequence number 823, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, a portion of exon 4 of SDC4 contains or consists of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from sequence number 822, and contains at least 75 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 822, and may include at least 75 nucleic acids. More preferably, a portion of exon 4 of the SDC4 includes or follows SEQ ID NO: 822 or its allele variant. Such short polynucleotide sequences are particularly useful for detecting the presence of a larger polynucleotide fusion between SDC4 and NRG1, and for establishing that such a fusion is an intraframe oncogenic fusion containing the EGF-like domain of NRG1.

[0343] Alternatively, a portion of exon 4 of SDC4 contains or comprises SEQ ID NO: 748 (or an allele variant of SEQ ID NO: 748) and comprises at least 199 nucleic acids. Preferably, a portion of exon 4 of SDC4 contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 748 or its allele variants, and comprises at least 199 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 748, and include at least 199 nucleic acids. In this alternative example, a portion of exon 4 of SDC4 more preferably includes or follows SEQ ID NO: 748 or its allele variant. Preferably, the portion of exon 2 of NRG1 in the fusion with SDC4 contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 126 or its allele variants, and contains at least one nucleic acid. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 of the nucleic acids in SEQ ID NO: 126, and may include at least the nucleic acid at position 1.

[0344] Preferably, any SDC4-NRG1 polynucleotide fusion provided herein is an intraframe fusion of SDC4 and NRG1. More preferably, the fusion is an intraframe fusion comprising exon 4 or a portion of exon 4 of SDC4 and exon 2 of NRG1 or a portion of exon 2 of NRG1. The intraframe fusion is preferably the fusion of SEQ ID NO: 824, or an allele variant thereof having at least 85% identity thereto, preferably at least 90%, 92%, 94%, 96%, or 98% identity thereto.

[0345] In alternatively preferred embodiments, the polynucleotide comprising a portion of exon 4 of SDC4 fused with a portion of exon 2 of NRG1 comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 824, including the nucleic acids at positions 75 and 76. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids in sequence number 824, and may include nucleic acids at least at positions 75 and 76. Sequence number 824 includes a junction between SDC4 and NRG1, and in particular, the junction is between the nucleic acid at position 75 derived from SDC4 and the nucleic acid at position 76 derived from NRG1. Preferably, the polynucleotide containing a portion of exon 4 of SDC4 fused with a portion of exon 2 of NRG1 has the polynucleotide sequence of SEQ ID NO: 824, or an allele variant thereof.

[0346] In preferred embodiments, a polynucleotide is provided that includes a polynucleotide according to SEQ ID NO: 824, or a polynucleotide comprising about 20, about 30, about 40, or all consecutive nucleic acids from SEQ ID NO: 824, preferably comprising nucleic acids at positions 75 and 76. The number of consecutive nucleic acids may be 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all nucleic acids from SEQ ID NO: 824, preferably comprising nucleic acids at least at positions 75 and 76.

[0347] Preferably, a polynucleotide comprising a portion of exon 2 of NRG1, or a portion of exon 4 of SDC4 fused with an allele variant thereof, or an allele variant thereof, further comprises a portion of a longer polynucleotide that comprises or encodes the EGF-like domain of NRG1. Abnormal cells comprising the SDC4 or a polynucleotide fusion expressing the polypeptide fusion contain or encode the EGF-like domain of NRG1. For rapid detection, diagnosis, or specific purposes, it may be sufficient to indicate that the fusion junction between SDC4 and NRG1 is within a frame and occurs at a position that contains the EGF-like domain of NRG1. The EGF-like domain is preferably the EGF-like domain according to SEQ ID NO: 163, or an allele variant thereof having at least 85% identity to SEQ ID NO: 163, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity thereto.

[0348] Preferably, exon 4 of SDC4 or a portion of its allele variant is 5' relative to exon 2 of NRG1 or a portion of its allele variant. This orientation at the nucleic acid level results in a fusion polypeptide product containing the N-terminus of SDC4 and the C-terminus of NRG1. The SDC4-NRG1 polynucleotide fusion provided herein also produces a protein fusion, where the portion from the N-terminus to the fusion junction is a polypeptide sequence from SDC4, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, with the NRG1 portion also providing its EGF-like domain. Thus, the SDC4-NRG1 fusion protein retains the EGF-like domain of NRG1 and retains the ability to promote the growth and survival of a subset of human cancers, including lung cancer, particularly non-small cell lung cancer.

[0349] When present in abnormal cells of a patient or subject, the polynucleotide fusion preferably further comprises any sequence 5' from exon 4 of SDC4 and any sequence 3' from exon 2 of NRG1, and it may be sufficient to have at least SEQ ID NOs. 748 and 126 present to enable detection of the fusion junction using a polynucleotide-based detection assay. The any sequence 5' from exon 4 of SDC4 comprises or consists of one or all of SEQ ID NOs. 745-747 (or any allele variant of SEQ ID NOs. 745-747), and the any sequence 3' from exon 2 of NRG1 comprises or consists of one or all of SEQ ID NOs. 127-137 (or any allele variant of SEQ ID NOs. 127-137).

[0350] SLC4A4-NRG1 polynucleotide fusion A polynucleotide fusion is also provided, comprising a portion of exon 14 of SLC4A4 fused with a portion of exon 6 of NRG1. Exon 14 of SLC4A4 is preferably the exon of SEQ ID NO: 780 or the allele variant of SEQ ID NO: 780, and exon 6 of NRG1 is preferably the exon of SEQ ID NO: 130 or the allele variant of SEQ ID NO: 130.

[0351] When present in abnormal cells of a patient or subject, the polynucleotide fusion preferably further comprises any sequence 5' from exon 14 of SLC4A4 and any sequence 3' from exon 6 of NRG1, and it may be sufficient to have at least SEQ ID NOs. 780 and 130 to enable detection of the fusion junction using a polynucleotide-based detection assay. The any sequence 5' from exon 14 of SLC4A4 comprises or consists of one or all of SEQ ID NOs. 767-779 (or any allele variant of SEQ ID NOs. 767-779), and the any sequence 3' from exon 6 of NRG1 comprises or consists of one or all of SEQ ID NOs. 131-137 (or any allele variant of SEQ ID NOs. 131-137).

[0352] Preferably, the allele variant of exon 14 of SLC4A4 has at least 85% identity with SEQ ID NO: 780, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity, and the allele variant of exon 6 of NRG1 has at least 85% identity with SEQ ID NO: 130, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0353] Preferably, a portion of exon 14 of SLC4A4 contains or conforms to sequence number 763, and its allele variants have at least 85% identity with respect to sequence number 763, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. A portion of exon 6 of NRG1 in the fusion with SLC4A4 is preferably a sequence conforming to or containing sequence number 764, and its allele variants have at least 85% identity with respect to sequence number 764, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, a portion of exon 14 of SLC4A4 contains or consists of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from sequence number 763, and contains at least the nucleic acid at position 75. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 763, and include at least the nucleic acid at position 75. More preferably, a portion of exon 14 of SLC4A4 includes or follows SEQ ID NO: 763 or its allele variant. Such short polynucleotide sequences are particularly useful for detecting the presence of larger polynucleotide fusions between SLC4A4 and NRG1, and for establishing that such fusions are intraframe oncogenic fusions containing the EGF-like domain of NRG1.

[0354] Alternatively, a portion of exon 14 of SLC4A4 contains or comprises SEQ ID NO: 780 (or an allele variant of SEQ ID NO: 780) and comprises at least 272 nucleic acids. Preferably, a portion of exon 14 of SLC4A4 contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 780 or its allele variants, and comprises at least 272 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids, and may include at least 272 nucleic acids. In this alternative example, a portion of exon 14 of SLC4A4 more preferably includes or follows sequence number 780 or its allele variant. Preferably, in the fusion with SLC4A4, a portion of exon 6 of NRG1 contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 130 or its allele variants, and contains at least one nucleic acid. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 of the nucleic acids in SEQ ID NO: 130, and may include at least the nucleic acid at position 1.

[0355] Preferably, any SLC4A4-NRG1 polynucleotide fusion provided herein is an intraframe fusion of SLC4A4 and NRG1. More preferably, the fusion is an intraframe fusion comprising exon 14 or a portion of exon 14 of SLC4A4 and exon 6 or a portion of exon 6 of NRG1. The intraframe fusion is preferably the fusion of SEQ ID NO: 765, or an allele variant thereof having at least 85% identity thereto, preferably at least 90%, 92%, 94%, 96%, or 98% identity thereto.

[0356] In alternatively preferred embodiments, the polynucleotide comprising a portion of exon 14 of SLC4A4 fused with a portion of exon 6 of NRG1 comprises 2 to about 10, about 20, about 30, or up to about 40, or all consecutive nucleic acids from sequence 765, including nucleic acids at positions 75 and 76. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids in sequence number 765, and may include nucleic acids at least at positions 75 and 76. Sequence number 765 includes a junction between SLC4A4 and NRG1, and in particular, the junction is between the nucleic acid at position 75 derived from SLC4A4 and the nucleic acid at position 76 derived from NRG1. Preferably, the polynucleotide containing a portion of exon 14 of SLC4A4 fused with a portion of exon 6 of NRG1 has the polynucleotide sequence of SEQ ID NO: 765, or an allele variant thereof.

[0357] In preferred embodiments, a polynucleotide is provided that includes a polynucleotide according to SEQ ID NO: 765, or a polynucleotide comprising about 20, about 30, about 40, or all consecutive nucleic acids from SEQ ID NO: 765, preferably comprising nucleic acids at positions 75 and 76. The number of consecutive nucleic acids may be 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all nucleic acids from SEQ ID NO: 765, preferably comprising nucleic acids at least at positions 75 and 76.

[0358] Preferably, a polynucleotide comprising a portion of exon 6 of NRG1, or a portion of exon 14 of SLC4A4 fused with an allele variant thereof, or an allele variant thereof, further comprises a portion of a longer polynucleotide that comprises or encodes the EGF-like domain of NRG1. Abnormal cells comprising SLC4A4 or a polynucleotide fusion expressing a polypeptide fusion contain or encode the EGF-like domain of NRG1. For rapid detection, diagnosis, or specific purposes, it may be sufficient to indicate that the fusion junction between SLC4A4 and NRG1 is within a frame and occurs at a position that contains the EGF-like domain of NRG1. The EGF-like domain is preferably an EGF-like domain according to SEQ ID NO: 163, or an allele variant thereof having at least 85% identity to SEQ ID NO: 163, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity thereto.

[0359] Preferably, exon 14 of SLC4A4 or a portion of its allele variant is 5' relative to exon 6 of NRG1 or a portion of its allele variant. This orientation at the nucleic acid level results in a fusion polypeptide product containing the N-terminus of SLC4A4 and the C-terminus of NRG1. The SLC4A4-NRG1 polynucleotide fusion provided herein also produces a protein fusion, where the portion from the N-terminus to the fusion junction is a polypeptide sequence from SLC4A4, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, with the NRG1 portion also providing its EGF-like domain. Thus, the SLC4A4-NRG1 fusion protein retains the EGF-like domain of NRG1 and retains the ability to promote the growth and survival of human cancers, particularly subsets of pancreatic cancer.

[0360] ZFAT-NRG1 polynucleotide fusion The disclosure also provides polynucleotides comprising a ZFAT nucleic acid sequence (or a portion of a ZFAT nucleic acid sequence) fused with an NRG1 nucleic acid sequence (or a portion of an NRG1 nucleic acid sequence). The fusion also includes allelic variants of the ZFAT and NRG1 nucleic acid sequences.

[0361] Preferably, the ZFAT nucleic acid sequence or a portion thereof contains or consists of any one of SEQ ID NOs. 830 to 846, or an allele variant of any one of SEQ ID NOs. 830 to 846, and the NRG1 nucleic acid sequence or a portion thereof contains or consists of any one of SEQ ID NOs. 125 to 138, or an allele variant of any one of SEQ ID NOs. 125 to 138. More preferably, the ZFAT nucleic acid sequence contains a portion of SEQ ID NOs. 846, or an allele variant of SEQ ID NOs. 846 preferably contains a portion of SEQ ID NOs. 138, or an allele variant of SEQ ID NOs. 138. SEQ ID NOs. 830 to 845 correspond to individual exons 1 to 16 of ZFAT according to NM_020863.4, respectively. SEQ ID NOs. 846 corresponds to individual exons 1 to 16 of ZFAT according to NM_020863.4. Sequence numbers 125-137 correspond to individual exons 1-13 of the NRG1 sequence according to NM_001159999.3, respectively. Sequence number 138 corresponds to exons 1-13 of NRG1 according to NM_001159999.3.

[0362] In a preferred embodiment, a portion of the ZFAT nucleic acid sequence includes 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids derived from any one of sequence numbers 830 to 846, or an allele variant of any one of sequence numbers 830 to 846, and a portion of the NRG1 nucleic acid sequence includes 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids derived from any one of sequence numbers 125 to 138, or an allele variant of any one of sequence numbers 125 to 138.

[0363] Preferably, the allele variant of the ZFAT nucleic acid sequence has at least 85% identity with any one of sequence numbers 830 to 846, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity with respect to it, and the allele variant of the NRG1 nucleic acid sequence has at least 85% identity with any one of sequence numbers 125 to 138, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity with respect to it.

[0364] Preferably, the ZFAT nucleic acid sequence or a portion thereof is 5' relative to the NRG1 nucleic acid sequence or a portion thereof.

[0365] Preferably, a polynucleotide containing an NRG1 nucleic acid sequence or a ZFAT nucleic acid sequence fused with a portion of the sequence, or a portion of the sequence, contains or encodes the EGF-like domain of NRG1.

[0366] Abnormal cells containing or expressing a ZFAT-NRG1 polynucleotide fusion contain or encode an EGF-like domain of NRG1. For detection, diagnosis, or specific purposes, it may be sufficient to indicate that the fusion junction between ZFAT and NRG1 is within a frame and occurs at a position that contains the EGF-like domain of NRG1. The EGF-like domain is preferably an EGF-like domain according to SEQ ID NO: 163, or an allele variant thereof having at least 85% identity to SEQ ID NO: 163, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0367] A polynucleotide fusion is also provided, comprising a portion of exon 12 of ZFAT fused with a portion of exon 6 of NRG1. The exon 12 of ZFAT is preferably the exon of SEQ ID NO: 841 or an allele variant of SEQ ID NO: 841, and the exon 6 of NRG1 is preferably the exon of SEQ ID NO: 130 or an allele variant of SEQ ID NO: 130.

[0368] When present in abnormal cells of a patient or subject, the polynucleotide fusion preferably further comprises any sequence 5' from exon 12 of ZFAT and any sequence 3' from exon 6 of NRG1, and it may be sufficient to have at least SEQ ID NOs. 841 and 130 to enable detection of the fusion junction using a polynucleotide-based detection assay. The any sequence 5' from exon 12 of ZFAT comprises or consists of one or all of SEQ ID NOs. 830-840 (or any allele variant of SEQ ID NOs. 830-840), and the any sequence 3' from exon 6 of NRG1 comprises or consists of one or all of SEQ ID NOs. 131-137 (or any allele variant of SEQ ID NOs. 131-137).

[0369] Preferably, the allele variant of exon 12 of ZFAT has at least 85% identity with SEQ ID NO: 841, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity, and the allele variant of exon 6 of NRG1 has at least 85% identity with SEQ ID NO: 130, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0370] Preferably, a portion of exon 12 of ZFAT contains or conforms to sequence number 826, and its allele variants have at least 85% identity with respect to sequence number 826, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. A portion of exon 6 of NRG1 in the fusion with ZFAT is preferably a sequence conforming to or containing sequence number 827, and its allele variants have at least 85% identity with respect to sequence number 827, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, a portion of exon 12 of ZFAT contains or consists of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from sequence number 826, and contains at least the nucleic acid at position 75. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 826, and may include at least 75 nucleic acids. More preferably, a portion of exon 12 of ZFAT includes or follows SEQ ID NO: 826 or its allele variant. Such short polynucleotide sequences are particularly useful for detecting the presence of larger polynucleotide fusions between ZFAT and NRG1, and for establishing that such fusions are intraframe oncogenic fusions containing the EGF-like domain of NRG1.

[0371] Alternatively, a portion of exon 12 of ZFAT contains or comprises SEQ ID NO: 841 (or an allele variant of SEQ ID NO: 841) and includes at least 139 nucleic acids. Preferably, a portion of exon 12 of ZFAT contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 841 or its allele variants, and includes at least 139 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 841, and include at least 139 nucleic acids. In this alternative example, a portion of exon 12 of ZFAT more preferably includes or follows SEQ ID NO: 841 or its allele variant. Preferably, a portion of exon 6 of NRG1 in the fusion with ZFAT contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 130 or its allele variants, and contains at least one nucleic acid. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 of the nucleic acids in SEQ ID NO: 130, and may include at least the nucleic acid at position 1.

[0372] In alternatively preferred embodiments, the polynucleotide comprising a portion of exon 12 of ZFAT fused with a portion of exon 6 of NRG1 comprises 2 to about 10, about 20, about 30, or up to about 40, or all consecutive nucleic acids from SEQ ID NO: 828, including nucleic acids at positions 75 and 76. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids in sequence number 828, and may include nucleic acids at least at positions 75 and 76. Sequence number 828 includes a junction between ZFAT and NRG1, and in particular, the junction is between the nucleic acid at position 75 derived from ZFAT and the nucleic acid at position 76 derived from NRG1. Preferably, the polynucleotide containing a portion of exon 12 of ZFAT fused with a portion of exon 6 of NRG1 has the polynucleotide sequence of SEQ ID NO: 828, or an allele variant thereof.

[0373] Preferably, any ZFAT-NRG1 polynucleotide fusion provided herein is an intraframe fusion of ZFAT and NRG1. More preferably, the fusion is an intraframe fusion comprising exon 12 or a portion of exon 12 of ZFAT and exon 6 or a portion of exon 6 of NRG1. The intraframe fusion is preferably the fusion of SEQ ID NO: 828, or an allele variant thereof having at least 85% identity thereto, preferably at least 90%, 92%, 94%, 96%, or 98% identity thereto.

[0374] Preferably, exon 12 of ZFAT or a portion of its allele variant is 5' relative to exon 6 of NRG1 or a portion of its allele variant. This orientation at the nucleic acid level results in a fusion polypeptide product containing the N-terminus of ZFAT and the C-terminus of NRG1. Furthermore, the ZFAT-NRG1 polynucleotide fusion provided herein produces a protein fusion in which the portion from the N-terminus to the fusion junction is a polypeptide sequence from ZFAT, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, with the NRG1 portion also providing its EGF-like domain. Thus, the ZFAT-NRG1 fusion protein retains the EGF-like domain of NRG1 and retains the ability to promote the growth and survival of human cancers, particularly subsets of non-small cell lung cancer.

[0375] DSCAML1-NRG1 polynucleotide fusion The disclosure also provides polynucleotides comprising a DSCAML1 nucleic acid sequence (or a portion of a DSCAML1 nucleic acid sequence) fused with an NRG1 nucleic acid sequence (or a portion of an NRG1 nucleic acid sequence). The fusion also includes allelic variants of the DSCAML1 and NRG1 nucleic acid sequences.

[0376] Preferably, the DSCAML1 nucleic acid sequence or a portion thereof includes or consists of any one of SEQ ID NOs. 870 to 903, or an allele variant of any one of SEQ ID NOs. 870 to 903, and the NRG1 nucleic acid sequence or a portion thereof includes or consists of any one of SEQ ID NOs. 125 to 138, or an allele variant of any one of SEQ ID NOs. 125 to 138. More preferably, the DSCAML1 nucleic acid sequence includes a portion of SEQ ID NOs. 903, or an allele variant of SEQ ID NOs. 903 corresponds to individual exons 1 to 33 of DSCAML1 according to NM_020693.4. Sequence numbers 125-137 correspond to individual exons 1-13 of the NRG1 sequence according to NM_001159999.3, respectively. Sequence number 138 corresponds to exons 1-13 of NRG1 according to NM_001159999.3.

[0377] In a preferred embodiment, a portion of the DSCAML1 nucleic acid sequence includes 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids derived from any one of sequence numbers 870 to 903, or an allele variant of any one of sequence numbers 870 to 903, and a portion of the NRG1 nucleic acid sequence includes 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids derived from any one of sequence numbers 125 to 138, or an allele variant of any one of sequence numbers 125 to 138.

[0378] Preferably, the allele variant of the DSCAML1 nucleic acid sequence has at least 85% identity with any one of sequence numbers 870 to 903, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity with respect to it, and the allele variant of the NRG1 nucleic acid sequence has at least 85% identity with any one of sequence numbers 125 to 138, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity with respect to it.

[0379] Preferably, the DSCAML1 nucleic acid sequence or a portion thereof is 5' relative to the NRG1 nucleic acid sequence or a portion thereof.

[0380] Preferably, a polynucleotide containing the DSCAML1 nucleic acid sequence or a portion of the sequence of NRG1 fused with the NRG1 nucleic acid sequence or a portion of the sequence contains or encodes the EGF-like domain of NRG1.

[0381] Abnormal cells containing or expressing a DSCAML1-NRG1 polynucleotide fusion contain or encode an EGF-like domain of NRG1. For detection, diagnosis, or specific purposes, it may be sufficient to indicate that the fusion junction between DSCAML1 and NRG1 is within a frame and occurs at a position that contains the EGF-like domain of NRG1. The EGF-like domain is preferably an EGF-like domain according to SEQ ID NO: 163, or an allele variant thereof having at least 85% identity to SEQ ID NO: 163, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0382] A polynucleotide fusion is also provided, comprising a portion of exon 3 of DSCAML1 fused with a portion of exon 2 of NRG1. The exon 3 of DSCAML1 is preferably the exon of SEQ ID NO: 872 or an allele variant of SEQ ID NO: 872, and the exon 2 of NRG1 is preferably the exon of SEQ ID NO: 126 or an allele variant of SEQ ID NO: 126.

[0383] When present in abnormal cells of a patient or subject, the polynucleotide fusion preferably further comprises any sequence 5' from exon 3 of DSCAML1 and any sequence 3' from exon 2 of NRG1, and it may be sufficient to have at least SEQ ID NOs. 872 and 126 present to enable detection of the fusion junction using a polynucleotide-based detection assay. The any sequence 5' from exon 3 of DSCAML1 comprises or consists of one or all of SEQ ID NOs. 870-871 (or any allele variant of SEQ ID NOs. 870-871), and the any sequence 3' from exon 2 of NRG1 comprises or consists of one or all of SEQ ID NOs. 127-137 (or any allele variant of SEQ ID NOs. 127-137).

[0384] Preferably, the allele variant of exon 3 of DSCAML1 has at least 85% identity with SEQ ID NO: 872, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity, and the allele variant of exon 2 of NRG1 has at least 85% identity with SEQ ID NO: 126, preferably at least 90% identity, 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0385] Preferably, a portion of exon 3 of DSCAML1 contains or conforms to sequence number 866, and its allele variants have at least 85% identity with respect to sequence number 866, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. A portion of exon 2 of NRG1 in the fusion with DSCAML1 is preferably a sequence conforming to or containing sequence number 867, and its allele variants have at least 85% identity with respect to sequence number 867, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, a portion of exon 3 of DSCAML1 contains or consists of 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from sequence number 866, and contains at least the nucleic acid at position 75. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 866, and include at least 75 nucleic acids. More preferably, a portion of exon 3 of DSCAML1 includes or follows SEQ ID NO: 866 or its allele variant. Such short polynucleotide sequences are particularly useful for detecting the presence of larger polynucleotide fusions between DSCAML1 and NRG1, and for establishing that such fusions are intraframe oncogenic fusions containing the EGF-like domain of NRG1.

[0386] Alternatively, a portion of exon 3 of DSCAML1 contains or comprises SEQ ID NO: 872 (or an allele variant of SEQ ID NO: 872) and comprises at least 147 nucleic acids. Preferably, a portion of exon 3 of DSCAML1 contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 872 or its allele variants, and comprises at least 147 nucleic acids. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids of SEQ ID NO: 872, and may include at least 147 nucleic acids. In this alternative example, a portion of exon 3 of DSCAML1 more preferably includes or follows SEQ ID NO: 872 or its allele variant. Preferably, a portion of exon 2 of NRG1 in the fusion with DSCAML1 contains or comprises 2 to about 10, about 20, about 30, or up to about 40, or even all consecutive nucleic acids from SEQ ID NO: 126 or its allele variant, and contains at least one nucleic acid. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 of the nucleic acids in SEQ ID NO: 126, and may include at least the nucleic acid at position 1.

[0387] In alternatively preferred embodiments, the polynucleotide comprising a portion of exon 3 of DSCAML1 fused with a portion of exon 2 of NRG1 comprises 2 to about 10, about 20, about 30, or up to about 40, or all consecutive nucleic acids from SEQ ID NO: 868, including nucleic acids at positions 75 and 76. The number of consecutive nucleic acids may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or all of the nucleic acids in sequence number 868, and may include nucleic acids at least at positions 75 and 76. Sequence number 868 includes a junction between DSCAML1 and NRG1, and in particular, the junction is between the nucleic acid at position 75 derived from DSCAML1 and the nucleic acid at position 76 derived from NRG1. Preferably, the polynucleotide containing a portion of exon 3 of DSCAML1 fused with a portion of exon 2 of NRG1 has the polynucleotide sequence of SEQ ID NO: 868, or an allele variant thereof.

[0388] Preferably, any DSCAML1-NRG1 polynucleotide fusion provided herein is an intraframe fusion of DSCAML1 and NRG1. More preferably, the fusion is an intraframe fusion comprising exon 3 or a portion of exon 3 of DSCAML1 and exon 2 or a portion of exon 2 of NRG1. The intraframe fusion is preferably the fusion of SEQ ID NO: 868, or an allele variant thereof having at least 85% identity thereto, preferably at least 90%, 92%, 94%, 96%, or 98% identity thereto.

[0389] Preferably, exon 3 of DSCAML1 or a portion of its allele variant is 5' relative to exon 2 of NRG1 or a portion of its allele variant. This orientation at the nucleic acid level results in a fusion polypeptide product containing the N-terminus of DSCAML1 and the C-terminus of NRG1. The DSCAML1-NRG1 polynucleotide fusion provided herein also produces a protein fusion, where the portion from the N-terminus to the fusion junction is a polypeptide sequence from DSCAML1, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, with the NRG1 portion also providing its EGF-like domain. Thus, the DSCAML1-NRG1 fusion protein retains the EGF-like domain of NRG1 and retains the ability to promote the growth and survival of human cancers, particularly adenocarcinomas, more specifically subsets of pancreatic ductal adenocarcinoma.

[0390] Each of the polynucleotide fusions referred to herein that contain NRG1, including VAPB-NRG1, CADM1-NRG1, CD44-NRG1, SLC3A2-NRG1, VTCN1-NRG1, CDH1-NRG1, CXADR-NRG1, GTF2E2-NRG1, CSMD1-NRG1, PTN-NRG1, ST14-NRG1, THBS1-NRG1, AGRN-NRG1, PVALB-NRG1, APP-NRG1, WRN-NRG1, DAAM1-NRG1, ASPH-NRG1, NOTCH2-NRG1, CD74-NRG1, SDC4-NRG1, SLC4A4-NRG1, ZFAT-NRG1, or DSCAML1-NRG1, is preferably isolated. Any method of the present invention preferably involves isolating one or more polynucleotide-containing components from a sample. One or more polynucleotide-containing components are typically isolated from any cells or cellular material in the sample.

[0391] NRG1 polypeptide fusion This disclosure provides polypeptide fusions containing NRG1, including VAPB-NRG1, CADM1-NRG1, CD44-NRG1, SLC3A2-NRG1, VTCN1-NRG1, CDH1-NRG1, CXADR-NRG1, GTF2E2-NRG1, CSMD1-NRG1, PTN-NRG1, ST14-NRG1, THBS1-NRG1, AGRN-NRG1, PVALB-NRG1, APP-NRG1, WRN-NRG1, ASPH-NRG1, NOTCH2-NRG1, CD74-NRG1, SDC4-NRG1, SLC4A4-NRG1, ZFAT-NRG1, and DSCAML1-NRG1. Specifically, such fusions are present in or have been identified in human patients diagnosed with cancer and are referred to in more detail in the following sections.

[0392] VAPB-NRG1 polypeptide fusion The present disclosure provides a polypeptide fusion encoded by a polynucleotide comprising a VAPB nucleic acid sequence (or a portion of a VAPB nucleic acid sequence) fused with an NRG1 nucleic acid sequence (or a portion of an NRG1 nucleic acid sequence). The VAPB nucleic acid sequence or portion thereof preferably comprises or consists of one of sequence numbers 24 to 30, or encodes an allele variant of any one of these sequence numbers. The NRG1 nucleic acid sequence or portion thereof preferably comprises or consists of one of sequence numbers 139 to 152, or encodes an allele variant of any one of these sequence numbers.

[0393] Any one VAPB allele variant from sequence numbers 24 to 30 preferably has at least 85% sequence identity with it, more preferably 90%, 92%, 94%, 96%, or even more preferably at least 98% sequence identity. Any one NRG1 allele variant from sequence numbers 139 to 152 preferably has at least 85% sequence identity with it, more preferably 90%, 92%, 94%, 96%, or even more preferably at least 98% sequence identity.

[0394] Preferably, a portion of the VAPB nucleic acid sequence of the fusion comprises or encodes a polypeptide portion of VAPB consisting of 8, 9, 10, 11, 12, 13, or 14 consecutive amino acids derived from any one of SEQ ID NOs. 24-30, or an allele variant of any one of SEQ ID NOs. 24-30. Preferably, a portion of the NRG1 nucleic acid sequence of the fusion comprises or encodes a polypeptide portion of NRG1 consisting of 8, 9, 10, 11, 12, 13, or 14 consecutive amino acids derived from any one of SEQ ID NOs. 139-152, or an allele variant of any one of SEQ ID NOs. 139-152.

[0395] Preferably, any VAPB-NRG1 polypeptide fusion of the present disclosure comprises one polypeptide sequence from SEQ ID NOs: 24-30 having one or more (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) point mutations that add, delete, or substitute any of the amino acids of the polypeptides of SEQ ID NOs: 24-30. Preferably, the polypeptide fusion comprises one polypeptide sequence from SEQ ID NOs: 24-34 having one, two, three, four, or five point mutations that add, delete, or substitute any of the amino acids of the polypeptides of SEQ ID NOs: 24-30. More preferably, the polynucleotide fusion comprises one polypeptide sequence from SEQ ID NOs: 24-30 having one, two, or three point mutations that add, delete, or substitute any of the amino acids of the polypeptides of SEQ ID NOs: 24-30.

[0396] In a preferred embodiment, a polypeptide fusion encoded by a polynucleotide comprising a portion of exon 1 of VAPB or an allele variant thereof, and a portion of exon 2 of NRG1 or an allele variant thereof, is provided. The polypeptide encoded by exon 1 of VAPB preferably comprises or consists of SEQ ID NO: 24 or an allele variant of SEQ ID NO: 24. The polypeptide encoded by exon 2 of NRG1 preferably comprises or consists of SEQ ID NO: 140 or an allele variant of SEQ ID NO: 140. Preferably, the polypeptide fusion further comprises any one or all of SEQ ID NOs: 141-151, or any allele variant of SEQ ID NOs: 141-151, respectively. SEQ ID NOs: 141-151 correspond to individual polypeptide sequences encoded by exons 3-13 of NRG1. The portion of exon 2 of NRG1 may also conform to or be an allele variant of SEQ ID NO: 154, which corresponds to the polypeptide sequence encoded by all of exons 2-13.

[0397] Preferably, the polypeptide encoded by a portion of exon 1 of VAPB contains or consists of 8, 9, 10, 11, 12, 13, or 14 consecutive amino acids derived from SEQ ID NO: 24, or from the allele variant SEQ ID NO: 24. The allele variant has at least 85% identity with respect to SEQ ID NO: 24, preferably at least 90%, 92%, 94%, 96%, or more preferably at least 98% sequence identity. Similarly, the polypeptide encoded by a portion of exon 2 of NRG1 contains or consists of 8, 9, 10, 11, 12, 13, o...

Claims

1. - A PVALB nucleic acid sequence fused with an NRG1 nucleic acid sequence or an allele variant of the NRG1 sequence, or an allele variant of the PVALB sequence, - An NRG1 nucleic acid sequence or an ASPH nucleic acid sequence fused with an allele variant of the NRG1 sequence or an allele variant of the ASPH sequence, - A DAAM1 nucleic acid sequence fused with an NRG1 nucleic acid sequence or an allele variant of the NRG1 sequence, or an allele variant of the DAAM1 sequence, - A ZFAT nucleic acid sequence fused with an NRG1 nucleic acid sequence or an allele variant of the NRG1 sequence, or an allele variant of the ZFAT sequence, - A polynucleotide comprising an NRG1 nucleic acid sequence or a DSCAML1 nucleic acid sequence fused with an allele variant of the NRG1 sequence, or an allele variant of the DSCAML1 sequence.

2. - The PVALB nucleic acid sequence contains or consists of any one of sequence numbers 439 to 444, or any allele variant of any one of sequence numbers 439 to 444, and the NRG1 nucleic acid sequence contains or consists of any one of sequence numbers 125 to 138. - The DAAM1 nucleic acid sequence contains or consists of any one of sequence numbers 606 to 631, or any allele variant of any one of sequence numbers 606 to 631, and the NRG1 nucleic acid sequence contains or consists of any one of sequence numbers 125 to 138. - The ZFAT nucleic acid sequence contains or consists of any one of sequence numbers 830 to 846, or any allele variant of any one of sequence numbers 830 to 846, and the NRG1 nucleic acid sequence contains or consists of any one of sequence numbers 125 to 138, or - The polynucleotide according to claim 1, wherein the DSCAML1 nucleic acid sequence contains or comprises any one of sequence numbers 870 to 903, or an allele variant of any one of sequence numbers 870 to 903, and the NRG1 nucleic acid sequence contains or comprises any one of sequence numbers 125 to 138.

3. The polynucleotide according to claim 1 or 2, wherein the PVALB, DAAM1, ZFAT, or DSCAML1 nucleic acid sequence (or the allele variant thereof) is 5' relative to the NRG1 nucleic acid sequence (or the allele variant thereof).

4. - The allele variant of the PVALB nucleic acid sequence has at least 85% identity, preferably at least 90% identity, and more preferably at least 95% sequence identity with any one of sequence numbers 439 to 444, and the allele variant of the NRG1 nucleic acid sequence has at least 85% identity, preferably at least 90% identity, and more preferably at least 95% sequence identity with any one of sequence numbers 125 to 138. - The allele variant of the DAAM1 nucleic acid sequence has at least 85% identity, preferably at least 90% identity, and more preferably at least 95% sequence identity with any one of sequence numbers 606 to 631, and the allele variant of the NRG1 nucleic acid sequence has at least 85% identity, preferably at least 90% identity, and more preferably at least 95% sequence identity with any one of sequence numbers 125 to 138. - The allele variant of the ZFAT nucleic acid sequence has at least 85% identity, preferably at least 90% identity, more preferably at least 95% sequence identity with any one of SEQ ID NOs: 830 to 846, and the allele variant of the NRG1 nucleic acid sequence has at least 85% identity, preferably at least 90% identity, more preferably at least 95% sequence identity with any one of SEQ ID NOs: 125 to 138, or - The polynucleotide according to any one of claims 1 to 3, wherein the allele variant of the DSCAML1 nucleic acid sequence has at least 85% identity, preferably at least 90% identity, and more preferably at least 95% sequence identity with any one of sequence numbers 870 to 903, and the allele variant of the NRG1 nucleic acid sequence has at least 85% identity, preferably at least 90% identity, and more preferably at least 95% sequence identity with any one of sequence numbers 125 to 138.

5. - The fusion of the PVALB nucleic acid and the NRG1 nucleic acid preferably contains 2 to about 40 consecutive nucleic acids from SEQ ID NO: 437, including nucleic acids at positions 102 and 103. - The fusion of the DAAM1 nucleic acid and the NRG1 nucleic acid preferably contains 2 to about 40 consecutive nucleic acids from SEQ ID NO: 605, including nucleic acids at positions 75 and 76. - The fusion of the ZFAT nucleic acid and the NRG1 nucleic acid preferably contains 2 to about 40 consecutive nucleic acids from SEQ ID NO: 828, including nucleic acids at positions 75 and 76, or - The polynucleotide according to any one of claims 1 to 4, wherein the fusion of the DSCAML1 nucleic acid and the NRG1 nucleic acid comprises 2 to about 40 consecutive nucleic acids from SEQ ID NO: 868, preferably including nucleic acids at positions 75 and 76.

6. The polynucleotide according to any one of claims 1 to 5, wherein the nucleic acid encoding the NRG1 protein sequence (or the allele variant thereof) includes or encodes the EGF-like domain of NRG1, preferably the EGF-like domain described in SEQ ID NO:

163.

7. - A portion of exon 1 of VAPB fused with a portion of exon 2 of NRG1 or a portion of an allele variant of exon 2, - A portion of exon 7 of CADM1 or a portion of an allele variant of exon 7, and a portion of exon 6 of NRG1 or a portion of an allele variant of exon 6, - A portion of exon 5 of CD44 or a portion of an allele variant of exon 5, and a portion of exon 2 of NRG1 or a portion of an allele variant of exon 2, - A portion of exon 1 of transcription version 6 of SLC3A2 or a portion of an allele variant of exon 1, and a portion of exon 5 of NRG1 or a portion of an allele variant of exon 5, - A portion of exon 2 of VTCN1 or a portion of an allele variant of exon 2, and a portion of exon 2 of NRG1 or a portion of an allele variant of exon 2, - A portion of exon 11 of CDH1 or a portion of an allele variant of exon 11, and a portion of exon 2 of NRG1 or a portion of an allele variant of exon 2, - A portion of exon 1 of CXADR or a portion of an allele variant of exon 1, and a portion of exon 2 of NRG1 or a portion of an allele variant of exon 2, - A portion of exon 2 of GTF2E2 or a portion of an allele variant of exon 1, and a portion of exon 2 of NRG1 or a portion of an allele variant of exon 2, - A portion of exon 23 of CSMD1 or a portion of an allele variant of exon 23, and a portion of exon 6 of NRG1 or a portion of an allele variant of exon 6, - A portion of exon 4 of PTN or a portion of an allele variant of exon 4, and a portion of exon 2 of NRG1 or a portion of an allele variant of exon 2, - A portion of exon 11 of ST14 or a portion of an allele variant of exon 11, and a portion of exon 6 of NRG1 or a portion of an allele variant of exon 6, - A portion of exon 9 of THBS1 or a portion of an allele variant of exon 9, and a portion of exon 6 of NRG1 or a portion of an allele variant of exon 6, - A portion of exon 12 of AGRN or a portion of an allele variant of exon 12, and a portion of exon 6 of NRG1 or a portion of an allele variant of exon 6, - A portion of exon 4 of PVALB or a portion of an allele variant of exon 4, and a portion of exon 6 of NRG1 or a portion of an allele variant of exon 6, - A portion of exon 2 of transcription version 3 of SLC3A2 or a portion of an allele variant of exon 2, and a portion of exon 6 of NRG1 or a portion of an allele variant of exon 6, - A portion of exon 14 of APP or a portion of an allele variant of exon 14, and a portion of exon 6 of NRG1 or a portion of an allele variant of exon 6, - A portion of exon 33 of WRN or a portion of an allele variant of exon 33, and a portion of exon 6 of NRG1 or a portion of an allele variant of exon 6, - A portion of exon 1 of DAAM1 or a portion of an allele variant of exon 1, and a portion of exon 1 of NRG1 or a portion of an allele variant of exon 1, - A portion of exon 22 of ASPH or a portion of an allele variant of exon 22, and a portion of exon 2 of NRG1 or a portion of an allele variant of exon 2, - A portion of exon 6 of NOTCH2 or a portion of an allele variant of exon 6, and a portion of exon 6 of NRG1 or a portion of an allele variant of exon 6, - A portion of exon 2 of CD74 or a portion of an allele variant of exon 2, and a portion of exon 2 of NRG1 or a portion of an allele variant of exon 2, - A portion of exon 2 of SDC4 or a portion of an allele variant of exon 2, and a portion of exon 2 of NRG1 or a portion of an allele variant of exon 2, - A portion of exon 5 of CD44 or a portion of an allele variant of exon 5, and a portion of exon 6 of NRG1 or a portion of an allele variant of exon 6, - A portion of exon 14 of SLC4A4 or a portion of an allele variant of exon 14, and a portion of exon 6 of NRG1 or a portion of an allele variant of exon 6, - A portion of exon 4 of SDC4 or a portion of an allele variant of exon 4, and a portion of exon 2 of NRG1 or a portion of an allele variant of exon 2, - A portion of exon 12 of ZFAT or a portion of an allele variant of exon 12, and a portion of exon 6 of NRG1 or a portion of an allele variant of exon 6, - A polynucleotide comprising a portion of exon 3 of DSCAML1 or a portion of an allele variant of exon 3, and a portion of exon 2 of NRG1 or a portion of an allele variant of exon 2.

8. Exon 1 of VAPB is the exon of sequence number 17, exon 7 of CADM1 is the exon of sequence number 39, exon 5 of CD44 is the exon of sequence number 65, exon 1 of SLC3A2 is the exon of sequence number 103, exon 2 of VTCN1 is the exon of sequence number 169, exon 11 of CDH1 is the exon of sequence number 198, exon 1 of CXADR is the exon of sequence number 219, and exon 2 of GTF2E2 is Exon 23 of CSMD1 is the exon of sequence number 279, exon 4 of PTN is the exon of sequence number 318, exon 11 of ST14 is the exon of sequence number 342, exon 9 of THBS1 is the exon of sequence number 386, exon 12 of AGRN is the exon of sequence number 416, exon 4 of PVALB is the exon of sequence number 442, and exon 2 of SLC3A2 is the exon of sequence number 457 Exon 1 of APP is the exon of SEQ ID NO: 501, exon 33 of WRN is the exon of SEQ ID NO: 562, exon 1 of DAAM1 is the exon of SEQ ID NO: 606, exon 22 of ASPH is the exon of SEQ ID NO: 658, exon 6 of NOTCH2 is the exon of SEQ ID NO: 700, exon 2 of CD74 is the exon of SEQ ID NO: 720, exon 2 of SDC4 is the exon of SEQ ID NO: 746, and CD44 The polynucleotide according to claim 7, wherein exon 5 of is the exon of SEQ ID NO: 65, exon 14 of SLC4A4 is the exon of SEQ ID NO: 780, exon 4 of SDC4 is the exon of SEQ ID NO: 748, exon 12 of ZFAT is the exon of SEQ ID NO: 841, exon 3 of DSCAM1 is the exon of SEQ ID NO: 872, and exons 1, 2, 5, and 6 of NRG1 are the exons of SEQ ID NO: 125, 126, 129, and 130, respectively.

9. - Exon 1 of VAPB or the portion of its allele variant is 5' relative to exon 2 of NRG1 or the portion of its allele variant, - Exon 7 of CADM1 or the portion of the allele variant thereof is 5' relative to exon 6 of NRG1 or the portion of the allele variant thereof, - Exon 5 of CD44 or the portion of its allele variant is 5' relative to exon 2 of NRG1 or the portion of its allele variant, - Exon 1 of SLC3A2 or the portion of its allele variant is 5' relative to exon 5 of NRG1 or the portion of its allele variant, - Exon 2 of VTCN1 or the portion of its allele variant is 5' relative to exon 2 of NRG1 or the portion of its allele variant, - Exon 11 of CDH1 or the portion of the allele variant thereof is 5' relative to exon 2 of NRG1 or the portion of the allele variant thereof, - Exon 1 of CXADR or the portion of its allele variant is 5' relative to exon 2 of NRG1 or the portion of its allele variant, - Exon 2 of GTF2E2 or the portion of its allele variant is 5' relative to exon 2 of NRG1 or the portion of its allele variant, - Exon 23 CSMD1 or the portion of its allele variant is 5' relative to exon 6 of NRG1 or the portion of its allele variant, - Exon 4 of PTN or the portion of its allele variant is 5' relative to exon 2 of NRG1 or the portion of its allele variant, - Exon 11 of ST14 or the portion of its allele variant is 5' relative to exon 6 of NRG1 or the portion of its allele variant, - Exon 9 of THBS1 or the portion of its allele variant is 5' relative to exon 6 of NRG1 or the portion of its allele variant, - Exon 12 of AGRN or the portion of its allele variant is 5' relative to exon 6 of NRG1 or the portion of its allele variant, - Exon 4 of PVALB or the portion of its allele variant is 5' relative to exon 6 of NRG1 or the portion of its allele variant, - Exon 2 of SCL3A2 or the portion of its allele variant is 5' relative to exon 6 of NRG1 or the portion of its allele variant, - Exon 14 of APP or the portion of the allele variant thereof is 5' relative to exon 6 of NRG1 or the portion of the allele variant of exon 6, - Exon 33 of WRN or the portion of the allele variant thereof is 5' relative to exon 6 of NRG1 or the portion of the allele variant of exon 6, - Exon 1 of DAAM1 or the portion of its allele variant is 5' relative to exon 1 of NRG1 or the portion of the allele variant of exon 1, - Exon 22 of ASPH or the portion of the allele variant thereof is 5' relative to exon 2 of NRG1 or the portion of the allele variant of exon 2, - Exon 6 of NOTCH2 or the portion of its allele variant is 5' relative to exon 6 of NRG1 or the portion of the allele variant of exon 6, - Exon 2 of CD74 or the portion of its allele variant is 5' relative to exon 2 of NRG1 or the portion of the allele variant of exon 2, - Exon 2 of SDC4 or the portion of its allele variant is 5' relative to exon 2 of NRG1 or the portion of the allele variant of exon 2, - Exon 5 of CD44 or the portion of the allele variant thereof is 5' with respect to exon 6 of NRG1 or the portion of the allele variant of exon 6, - Exon 14 of SLC4A4 or the portion of its allele variant is 5' relative to exon 6 of NRG1 or the portion of the allele variant of exon 6, - Exon 4 of SDC4 or a portion of its allele variant is 5' relative to exon 2 of NRG1 or the portion of the allele variant of exon 2, - Exon 12 of ZFAT or the portion of the allele variant thereof is 5' relative to exon 6 of NRG1 or the portion of the allele variant of exon 6, and - The polynucleotide according to claim 7 or 8, wherein exon 3 of DSCAML1 or the portion of the allele variant thereof is 5' relative to exon 2 of NRG1 or the portion of the allele variant of exon 2.

10. - The allele variant of exon 1 of VAPB has at least 85% identity with SEQ ID NO: 17, preferably at least 90%, 92%, 94%, 96%, or even 98% identity with respect to it. - The allele variant of exon 7 of CADM1 has at least 85% identity with SEQ ID NO: 39, preferably at least 90%, 92%, 94%, 96%, or even 98% identity with respect to it. - The allele variant of exon 5 of CD44 has at least 85% identity with SEQ ID NO: 65, preferably at least 90%, 92%, 94%, 96%, or even 98% identity with respect to it. - The allele variant of exon 1 of SLC3A2 has at least 85% identity with SEQ ID NO: 103, preferably at least 90%, 92%, 94%, 96%, or even 98% identity with respect to it. - The allele variant of exon 2 of VTCN1 has at least 85% identity with SEQ ID NO: 169, preferably at least 90%, 92%, 94%, 96%, or even 98% identity with respect to it. - The allele variant of exon 11 of CDH1 has at least 85% identity with SEQ ID NO: 198, preferably at least 90%, 92%, 94%, 96%, or even 98% identity with respect to it. - The allele variant of exon 2 of NRG1 has at least 85% identity with SEQ ID NO: 126, preferably at least 90%, 92%, 94%, 96%, or even 98% identity with respect to it. - The allele variant of exon 5 of NRG1 has at least 85% identity with SEQ ID NO: 129, preferably at least 90%, 92%, 94%, 96%, or even 98% identity with respect to it. - The allele variant of exon 6 of NRG1 has at least 85% identity with SEQ ID NO: 130, preferably at least 90%, 92%, 94%, 96%, or even 98% identity with respect to it. - The allele variant of exon 1 of CXADR has at least 85% identity with SEQ ID NO: 219, preferably at least 90%, 92%, 94%, 96%, or even 98% identity with respect to it. - The allele variant of exon 2 of GTF2E2 has at least 85% identity with SEQ ID NO: 236, preferably at least 90%, 92%, 94%, 96%, or even 98% identity with respect to it. - The allele variant of exon 23 of CSMD1 has at least 85% identity with SEQ ID NO: 279, preferably at least 90%, 92%, 94%, 96%, or even 98% identity with respect to it. - The allele variant of exon 4 of PTN has at least 85% identity with SEQ ID NO: 318, preferably at least 90%, 92%, 94%, 96%, or even 98% identity with respect to it. - The allele variant of exon 11 of ST14 has at least 85% identity with SEQ ID NO: 342, preferably at least 90%, 92%, 94%, 96%, or even 98% identity with respect to it. - The allele variant of exon 9 of THBS1 has at least 85% identity with SEQ ID NO: 386, preferably at least 90%, 92%, 94%, 96%, or even 98% identity with respect to it. - The allele variant of exon 12 of AGRN has at least 85% identity with SEQ ID NO: 416, preferably at least 90%, 92%, 94%, 96%, or even 98% identity with respect to it. - The allele variant of exon 4 of PVALB has at least 85% identity with SEQ ID NO: 442, preferably at least 90%, 92%, 94%, 96%, or even 98% identity with respect to it. - The allele variant of exon 2 of SCL3A2 has at least 85% identity with SEQ ID NO: 457, preferably at least 90%, 92%, 94%, 96%, or even 98% identity with respect to it. - The allele variant of exon 14 of APP has at least 85% identity with SEQ ID NO: 501, preferably at least 90%, 92%, 94%, 96%, or even 98% identity with respect to it. - The allele variant of exon 33 of WRN has at least 85% identity with SEQ ID NO: 562, preferably at least 90%, 92%, 94%, 96%, or even 98% identity with respect to it. - The allele variant of exon 1 of DAAM1 has at least 85% identity with SEQ ID NO: 606, preferably at least 90%, 92%, 94%, 96%, or even 98% identity with respect to it. - The allele variant of exon 1 of NRG1 has at least 85% identity with SEQ ID NO: 125, preferably at least 90%, 92%, 94%, 96%, or even 98% identity with respect to it. - The allele variant of exon 22 of ASPH has at least 85% identity with SEQ ID NO: 658, preferably at least 90%, 92%, 94%, 96%, or even 98% identity with respect to it. - The allele variant of exon 6 of NOTCH2 has at least 85% identity with SEQ ID NO: 700, preferably at least 90%, 92%, 94%, 96%, or even 98% identity with respect to it. - The allele variant of exon 2 of CD74 has at least 85% identity with SEQ ID NO: 720, preferably at least 90%, 92%, 94%, 96%, or even 98% identity with respect to it. - The allele variant of exon 2 of SDC4 has at least 85% identity with SEQ ID NO: 746, preferably at least 90%, 92%, 94%, 96%, or even 98% identity with respect to it. - The allele variant of exon 5 of CD44 has at least 85% identity with SEQ ID NO: 65, preferably at least 90%, 92%, 94%, 96%, or even 98% identity with respect to it. - The allele variant of exon 14 of SLC4A4 has at least 85% identity with SEQ ID NO: 780, preferably at least 90%, 92%, 94%, 96%, or even 98% identity with respect to it. - The allele variant of exon 4 of SDC4 has at least 85% identity with SEQ ID NO: 748, preferably at least 90%, 92%, 94%, 96%, or even 98% identity with respect to it. - The allele variant of exon 12 of ZFAT has at least 85% identity with SEQ ID NO: 841, preferably at least 90%, 92%, 94%, 96%, or even 98% identity with respect to it, and - The polynucleotide according to any one of claims 7 to 9, wherein the allele variant of exon 3 of DSCAML1 has at least 85% identity with respect to SEQ ID NO: 872, preferably at least 90%, 92%, 94%, 96%, or even more than 98% identity therewith.

11. - The fusion of VAPB and NRG1 contains 2 to about 40 consecutive nucleic acids from SEQ ID NO: 3, including the nucleic acids at positions 43 and 44. - The fusion of CADM1 and NRG1 contains 2 to about 40 consecutive nucleic acids from SEQ ID NO: 7, including the nucleic acids at positions 53 and 54. - The fusion of CD44 and NRG1 contains 2 to about 40 consecutive nucleic acids from SEQ ID NO: 11, including the nucleic acids at positions 52 and 53. - The fusion of SLC3A2 and NRG1 contains 2 to about 40 consecutive nucleic acids from SEQ ID NO: 15, including the nucleic acids at positions 53 and 54. - The fusion of VTCN1 and NRG1 contains 2 to about 40 consecutive nucleic acids from SEQ ID NO: 166, including nucleic acids at positions 65 and 66. - The fusion of CDH1 and NRG1 contains 2 to about 40 consecutive nucleic acids from SEQ ID NO: 186, including the nucleic acids at positions 119 and 120. - The fusion of CXADR and NRG1 contains 2 to about 40 consecutive nucleic acids from SEQ ID NO: 217, including the nucleic acids at positions 43 and 44. - The fusion of GTF2E2 and NRG1 contains 2 to about 40 consecutive nucleic acids from SEQ ID NO: 233, including the nucleic acids at positions 141 and 142. - The fusion of CSMD1 and NRG1 contains 2 to about 40 consecutive nucleic acids from SEQ ID NO: 255, including the nucleic acids at positions 88 and 89. - The fusion of PTN and NRG1 contains 2 to about 40 consecutive nucleic acids from SEQ ID NO: 313, including nucleic acids at positions 102 and 103. - The fusion of ST14 and NRG1 contains 2 to about 40 consecutive nucleic acids from SEQ ID NO: 330, including the nucleic acids at positions 95 and 96. - The fusion of THBS1 and NRG1 contains 2 to about 40 consecutive nucleic acids from SEQ ID NO: 376, including the nucleic acids at positions 56 and 57. - The fusion of AGRN and NRG1 contains 2 to about 40 consecutive nucleic acids from SEQ ID NO: 403, including nucleic acids at positions 106 and 107. - The fusion of PVALB and NRG1 contains 2 to about 40 consecutive nucleic acids from SEQ ID NO: 437, including the nucleic acids at positions 102 and 103. - The fusion of SLC3A2 and NRG1 contains 2 to about 40 consecutive nucleic acids from SEQ ID NO: 454, including the nucleic acids at positions 93 and 94. - The fusion of APP and NRG1 contains 2 to about 40 consecutive nucleic acids from sequence number 486, including the nucleic acids at positions 54 and 55. - The fusion of WRN and NRG1 contains 2 to about 40 consecutive nucleic acids from SEQ ID NO: 528, including nucleic acids at positions 96 and 97. - The fusion of DAAM1 and NRG1 contains 2 to about 40 consecutive nucleic acids from SEQ ID NO: 605, including the nucleic acids at positions 75 and 76. - The fusion of ASPH and NRG1 contains 2 to about 40 consecutive nucleic acids from SEQ ID NO: 635, including the nucleic acids at positions 75 and 76. - The fusion of NOTCH2 and NRG1 contains 2 to about 40 consecutive nucleic acids from SEQ ID NO: 693, including the nucleic acids at positions 75 and 76. - The fusion of CD74 and NRG1 contains 2 to about 40 consecutive nucleic acids from SEQ ID NO: 717, including the nucleic acids at positions 75 and 76. - The fusion of SDC4 and NRG1 contains 2 to about 40 consecutive nucleic acids from SEQ ID NO: 743, including nucleic acids at positions 75 and 76. - The fusion of CD44 and NRG1 contains 2 to about 40 consecutive nucleic acids from SEQ ID NO: 761, including the nucleic acids at positions 75 and 76. - The fusion of SLC4A4 and NRG1 contains 2 to about 40 consecutive nucleic acids from SEQ ID NO: 765, including nucleic acids at positions 75 and 76. - The fusion of SDC4 and NRG1 contains 2 to about 40 consecutive nucleic acids from SEQ ID NO: 824, including nucleic acids at positions 75 and 76. - The fusion of ZFAT and NRG1 contains 2 to approximately 40 consecutive nucleic acids from SEQ ID NO: 828, including the nucleic acids at positions 75 and 76, and - The polynucleotide according to any one of claims 7 to 10, wherein the fusion of DSCAM1 and NRG1 comprises 2 to about 40 consecutive nucleic acids from SEQ ID NO: 868, including nucleic acids at positions 75 and 76.

12. - The fusion of VAPB and NRG1 includes Sequence ID No. 3 or its allele variant, - The fusion of CADM1 and NRG1 includes SEQ ID NO: 7 or its allele variant, - The fusion of CD44 and NRG1 includes SEQ ID NO: 11 or its allele variant, - The fusion of SLC3A2 and NRG1 includes SEQ ID NO: 15 or its allele variant, - The fusion of VTCN1 and NRG1 includes SEQ ID NO: 166 or its allele variant, - The fusion of CDH1 and NRG1 includes SEQ ID NO: 186 or its allele variant, - The fusion of CXADR and NRG1 includes SEQ ID NO: 217 or its allele variant, - The fusion of GTF2E2 and NRG1 includes SEQ ID NO: 233 or its allele variant, - The fusion of CSMD1 and NRG1 includes SEQ ID NO: 255 or its allele variant, - The fusion of PTN and NRG1 includes SEQ ID NO: 313 or its allele variant, - The fusion of ST14 and NRG1 includes SEQ ID NO: 330 or its allele variant, - The fusion of THBS1 and NRG1 includes SEQ ID NO: 376 or its allele variant, - The fusion of AGRN and NRG1 includes SEQ ID NO: 403 or its allele variant, - The fusion of PVALB and NRG1 includes SEQ ID NO: 437 or its allele variant, - The fusion of SLC3A2 and NRG1 includes SEQ ID NO: 454 or its allele variant, - The fusion of APP and NRG1 includes Sequence ID No. 486 or its allele variant, - The fusion of WRN and NRG1 includes SEQ ID NO: 528 or its allele variant, - The fusion of DAAM1 and NRG1 includes SEQ ID NO: 605 or its allele variant, - The fusion of ASPH and NRG1 includes SEQ ID NO: 635 or its allele variant, - The fusion of NOTCH2 and NRG1 includes SEQ ID NO: 693 or its allele variant, - The fusion of CD74 and NRG1 includes SEQ ID NO: 717 or its allele variant, - The fusion of SDC4 and NRG1 includes SEQ ID NO: 743 or its allele variant, - The fusion of CD44 and NRG1 includes SEQ ID NO: 761 or its allele variant, - The fusion of SLC4A4 and NRG1 includes SEQ ID NO: 765 or its allele variant, - The fusion of SDC4 and NRG1 includes SEQ ID NO: 824 or its allele variant, - The fusion of ZFAT and NRG1 includes SEQ ID NO: 828 or its allele variant, and - The polynucleotide according to any one of claims 7 to 11, wherein the fusion of DSCAML1 and NRG1 includes SEQ ID NO: 868 or its allele variant.

13. - The aforementioned portion of exon 1 of VAPB is either sequence number 1 or allele variant sequence number 1, or contains the same. - The portion of exon 7 of CADM1 is either sequence number 5 or an allele variant of sequence number 5, or contains the same. - The portion of exon 5 of CD44 is either sequence number 9 or allele variant sequence number 9, or contains the same. - The portion of exon 1 of SLC3A2 is either sequence number 13 or allele variant sequence number 13, or contains the same. - The portion of exon 2 of VTCN1 is sequence number 164 or allele variant sequence number 164, or contains the same. - The aforementioned portion of exon 11 of CDH1 is sequence number 184 or allele variant sequence number 184, or contains the same. - The portion of exon 1 of CXADR is sequence number 215 or allele variant sequence number 215, or contains the same. - The portion of exon 2 of GTF2E2 is SEQ ID NO: 231 or allele variant SEQ ID NO: 231, or contains the same. - The portion of exon 23 of CSMD1 is sequence number 253 or allele variant sequence number 253, or includes the same. - The portion of exon 4 of PTN is sequence number 311 or allele variant sequence number 311, or contains the same. - The portion of exon 11 of ST14 is or contains SEQ ID NO: 328 or allele variant SEQ ID NO:

328. - The portion of exon 9 of THBS1 is sequence number 374 or allele variant sequence number 374, or contains the same. - The portion of exon 12 of AGRN is sequence number 401 or allele variant sequence number 401, or contains the same. - The portion of exon 4 of PVALB is sequence number 435 or allele variant sequence number 435, or contains the same. - The portion of exon 2 of SLC3A2 is sequence number 452 or allele variant sequence number 452, or contains the same. - The portion of exon 2 of NRG1 is SEQ ID NO: 165 or allele variant SEQ ID NO: 165, or contains the same. - The portion of exon 5 of NRG1 is either sequence number 14 or allele variant sequence number 14, or contains the same. - The portion of exon 6 of NRG1 is either SEQ ID NO: 6 or its allele variant, or contains the same. - The portion of exon 14 of APP is either sequence number 484 or its allele variant, or contains the same. - The portion of exon 33 of WRN is either sequence number 526 or its allele variant, or contains the same. - The aforementioned portion of exon 1 of DAAM1 is either sequence number 603 or its allele variant, or contains the same. - The portion of exon 22 of ASPH is either sequence number 633 or its allele variant, or contains the same. - The portion of exon 6 of NOTCH2 is either sequence number 691 or its allele variant, or contains the same. - The portion of exon 2 of CD74 is either sequence number 715 or its allele variant, or contains the same. - The portion of exon 2 of SDC4 is either sequence number 741 or its allele variant, or contains the same. - The portion of exon 5 of CD44 is either sequence number 759 or its allele variant, or contains the same. - The portion of exon 14 of SLC4A4 is either sequence number 763 or its allele variant, or contains the same. - The portion of exon 4 of SDC4 is either sequence number 822 or its allele variant, or contains the same. - The portion of exon 12 of ZFAT is either SEQ ID NO: 826 or its allele variant, or contains the same. - The portion of exon 3 of DSCAML1 is either sequence number 866 or its allele variant, or contains the same, - The polynucleotide according to any one of claims 7 to 12, wherein the portion of exon 1 of NRG1 is or comprises SEQ ID NO: 604 or an allele variant thereof.

14. - The fusion of VAPB and NRG1 includes a fusion junction between exon 1 of VAPB and exon 2 of NRG1, preferably a junction between the nucleic acid at position 43 of VAPB and the nucleic acid at position 44 of NRG1, - The fusion of CADM1 and NRG1 includes a fusion junction between exon 7 of CADM1 and exon 6 of NRG1, preferably a junction between the nucleic acid at position 53 of CADM1 and the nucleic acid at position 54 of NRG1, - The fusion of CD44 and NRG1 includes a fusion junction between exon 5 of CD44 and exon 2 of NRG1, preferably a junction between the nucleic acid at position 52 of CD44 and the nucleic acid at position 53 of NRG1 in Sequence ID No.

11. - The fusion of SLC3A2 and NRG1 includes a fusion junction between exon 1 of SLC3A2 and exon 5 of NRG1, preferably a junction between the nucleic acid at position 53 of SLC3A2 and the nucleic acid at position 54 of NRG1, - The fusion of VTCN1 and NRG1 includes a fusion junction between exon 2 of VTCN1 and exon 2 of NRG1, preferably a junction between the nucleic acid at position 65 of VTCN1 and the nucleic acid at position 66 of NRG1 of Sequence ID No.

166. - The fusion of CDH1 and NRG1 includes a fusion junction between exon 11 of CDH1 and exon 2 of NRG1, preferably a junction between the nucleic acid at position 119 of CDH1 and the nucleic acid at position 120 of NRG1 in Sequence ID No.

186. - The fusion of CXADR and NRG1 includes a fusion junction between exon 1 of CXADR and exon 2 of NRG1, preferably a junction between the nucleic acid at position 43 of CXADR and the nucleic acid at position 44 of NRG1 of Sequence ID No.

217. - The fusion of GTF2E2 and NRG1 includes a fusion junction between exon 2 of GTF2E2 and exon 2 of NRG1, preferably a junction between the nucleic acid at position 141 of GTF2E2 and the nucleic acid at position 142 of NRG1, - The fusion of CSMD1 and NRG1 includes a fusion junction between exon 23 of CSMD1 and exon 6 of NRG1, preferably a junction between the nucleic acid at position 88 of CSMD1 and the nucleic acid at position 89 of NRG1 of Sequence ID No.

255. - The fusion of PTN and NRG1 includes a fusion junction between exon 4 of PTN and exon 2 of NRG1, preferably a junction between the nucleic acid at position 102 of PTN and the nucleic acid at position 103 of NRG1, - The fusion of ST14 and NRG1 includes a fusion junction between exon 11 of ST14 and exon 6 of NRG1, preferably a junction between the nucleic acid at position 95 of ST14 and the nucleic acid at position 96 of NRG1 of Sequence ID No.

330. - The fusion of THBS1 and NRG1 includes a fusion junction between exon 9 of THBS1 and exon 6 of NRG1, preferably a junction between the nucleic acid at position 56 of THBS1 and the nucleic acid at position 57 of NRG1 of Sequence ID No.

376. - The fusion of AGRN and NRG1 includes a fusion junction between exon 12 of AGRN and exon 6 of NRG1, preferably a junction between the nucleic acid at position 106 of AGRN and the nucleic acid at position 107 of NRG1, - The fusion of PVALB and NRG1 includes a fusion junction between exon 4 of PVALB and exon 6 of NRG1, preferably a junction between the nucleic acid at position 102 of PVALB and the nucleic acid at position 103 of NRG1 of Sequence ID No.

437. - The fusion of SLC3A2 and NRG1 includes a fusion junction between exon 2 of SLC3A2 and exon 6 of NRG1, preferably a junction between the nucleic acid at position 93 of SLC3A2 and the nucleic acid at position 94 of NRG1, - The fusion of APP and NRG1 includes a fusion junction between exon 14 of APP and exon 6 of NRG1, preferably a junction between the nucleic acid at position 54 of APP and the nucleic acid at position 55 of NRG1 of Sequence ID No.

486. - The fusion of WRN and NRG1 includes a fusion junction between exon 33 of WRN and exon 6 of NRG1, preferably a junction between the nucleic acid at position 96 of WRN and the nucleic acid at position 97 of NRG1, - The fusion of DAAM1 and NRG1 includes a fusion junction between exon 1 of DAAM1 and exon 1 of NRG1, preferably a junction between the nucleic acid at position 75 of DAAM1 and the nucleic acid at position 76 of NRG1 of Sequence ID No.

605. - The fusion of ASPH and NRG1 includes a fusion junction between exon 22 of ASPH and exon 2 of NRG1, preferably a junction between the nucleic acid at position 75 of ASPH and the nucleic acid at position 76 of NRG1, - The fusion of NOTCH2 and NRG1 includes a fusion junction between exon 6 of NOTCH2 and exon 6 of NRG1, preferably a junction between the nucleic acid at position 75 of NOTCH2 and the nucleic acid at position 76 of NRG1 of Sequence ID No.

693. - The fusion of CD74 and NRG1 includes a fusion junction between exon 2 of CD74 and exon 2 of NRG1, preferably a junction between the nucleic acid at position 75 of CD74 and the nucleic acid at position 76 of NRG1 in Sequence ID No.

717. - The fusion of SDC4 and NRG1 includes a fusion junction between exon 2 of SDC4 and exon 2 of NRG1, preferably a junction between the nucleic acid at position 75 of SDC4 and the nucleic acid at position 76 of NRG1, - The fusion of CD44 and NRG1 includes a fusion junction between exon 5 of CD44 and exon 6 of NRG1, preferably a junction between the nucleic acid at position 75 of CD44 and the nucleic acid at position 76 of NRG1, - The fusion of SLC4A4 and NRG1 includes a fusion junction between exon 14 of SLC4A4 and exon 6 of NRG1, preferably a junction between the nucleic acid at position 75 of SLC4A4 and the nucleic acid at position 76 of NRG1, - The fusion of SDC4 and NRG1 includes a fusion junction between exon 4 of SDC4 and exon 2 of NRG1, preferably a junction between the nucleic acid at position 75 of SDC4 and the nucleic acid at position 76 of NRG1 of SEQ ID NO:

824. - The fusion of ZFAT and NRG1 includes a fusion junction between exon 12 of ZFAT and exon 6 of NRG1, preferably a junction between the nucleic acid at position 75 of ZFAT and the nucleic acid at position 76 of NRG1, and - The polynucleotide according to any one of claims 7 to 12, wherein the fusion of DSCAM1 and NRG1 includes a fusion junction between exon 3 of DSCAM1 and exon 2 of NRG1, preferably a junction between the nucleic acid at position 75 of DSCAM1 and the nucleic acid at position 76 of NRG1 of SEQ ID NO:

868.

15. A polynucleotide according to any one of the prior claims, which is isolated or purified.

16. The polynucleotide according to any one of the prior claims, wherein any one of the aforementioned fusions is an intraframe fusion.

17. The polynucleotide according to any one of the prior claims, wherein the polynucleotide is a mammalian polynucleotide, preferably a human polynucleotide.

18. A polypeptide fusion encoded by a polynucleotide as described in any one of the prior claims.

19. A vector comprising a polynucleotide according to any one of claims 1 to 17.

20. Recombinant host cells comprising a polynucleotide according to any one of claims 1 to 17 or a vector according to claim 19.

21. A method for producing a polypeptide fusion according to claim 18, comprising maintaining the host cell according to claim 20 under conditions suitable for the expression of the polynucleotide contained by the host cell, thereby expressing the polynucleotide, producing a polypeptide fusion, and subsequently isolating or purifying the polypeptide fusion.

22. A method for producing recombinant host cells, comprising introducing the vector described in claim 19 into host cells.

23. A detection assay comprising a nucleic acid probe, primer, or primer pair for detecting the presence of a polynucleotide fusion according to any one of claims 1 to 17.

24. A nucleic acid probe, primer, or primer pair for detecting a polynucleotide fusion according to any one of claims 1 to 17.

25. A nucleic acid probe, primer, or primer pair according to claim 24, having a length of 10 to 40 nucleotides.

26. The detected fusion is - A fusion of VAPB and NRG1 containing or comprising SEQ ID NO: 3, preferably containing nucleic acids at positions 43 and 44, - A fusion of CADM1 and NRG1 containing or comprising SEQ ID NO: 7, preferably containing nucleic acids at positions 53 and 54, - A fusion of CD44 and NRG1 containing or comprising SEQ ID NO: 11, preferably containing nucleic acids at positions 52 and 53, - A fusion of SLC3A2 and NRG1 containing or comprising SEQ ID NO: 15, preferably containing nucleic acids at positions 53 and 54, - A fusion of VTCN1 and NRG1 containing or comprising SEQ ID NO: 166, preferably containing nucleic acids at positions 65 and 66, - A fusion of CDH1 and NRG1 containing or comprising SEQ ID NO: 186, preferably containing nucleic acids at positions 119 and 120, - A fusion of CXADR and NRG1 containing or comprising SEQ ID NO: 217, preferably containing nucleic acids at positions 43 and 44, - A fusion of GTF2E2 and NRG1 containing or comprising SEQ ID NO: 233, preferably containing nucleic acids at positions 141 and 142, - A fusion of CSMD1 and NRG1 containing or comprising SEQ ID NO: 255, preferably containing nucleic acids at positions 88 and 89, - A fusion of PTN and NRG1 containing or comprising SEQ ID NO: 313, preferably containing nucleic acids at positions 102 and 103, - A fusion of ST14 and NRG1 containing or comprising SEQ ID NO: 330, preferably containing nucleic acids at positions 95 and 96, - A fusion of THBS1 and NRG1 containing or comprising SEQ ID NO: 376, preferably containing nucleic acids at positions 56 and 57, - A fusion of AGRN and NRG1 containing or comprising SEQ ID NO: 403, preferably containing nucleic acids at positions 106 and 107, - A fusion of PVALB and NRG1 containing or comprising SEQ ID NO: 437, preferably containing nucleic acids at positions 102 and 103, - A fusion of SLC3A2 and NRG1 containing or comprising SEQ ID NO: 454, preferably containing nucleic acids at positions 93 and 94, - A fusion of APP and NRG1 containing or comprising SEQ ID NO: 486, preferably containing nucleic acids at positions 54 and 55, - A fusion of WRN and NRG1 containing or comprising SEQ ID NO: 528, preferably containing nucleic acids at positions 96 and 97, - A fusion of DAAM1 and NRG1 containing or comprising SEQ ID NO: 605, preferably containing nucleic acids at positions 75 and 76, - A fusion of ASPH and NRG1 containing or comprising SEQ ID NO: 635, preferably containing nucleic acids at positions 75 and 76, - A fusion of NOTCH2 and NRG1 containing or comprising SEQ ID NO: 693, preferably containing nucleic acids at positions 75 and 76, - A fusion of CD74 and NRG1 containing or comprising SEQ ID NO: 717, preferably containing nucleic acids at positions 75 and 76, - A fusion of SDC4 and NRG1 containing or comprising SEQ ID NO: 743, preferably containing nucleic acids at positions 75 and 76, - A fusion of CD44 and NRG1 containing or comprising SEQ ID NO: 761, preferably containing nucleic acids at positions 75 and 76, - A fusion of SLC4A4 and NRG1 containing or comprising SEQ ID NO: 765, preferably containing nucleic acids at positions 75 and 76, - A fusion of SDC4 and NRG1 containing or comprising SEQ ID NO: 824, preferably containing nucleic acids at positions 75 and 76, - A fusion of ZFAT and NRG1 containing or comprising SEQ ID NO: 828, preferably containing nucleic acids at positions 75 and 76, and - A nucleic acid probe, primer, or primer pair according to claim 24 or 25, comprising a fusion of DSCAM1 and NRG1 containing or comprising SEQ ID NO: 868, preferably comprising nucleic acids at positions 75 and 76.

27. - The probe, primer, or primer pair for detecting the fusion of VAPB and NRG1 specifically hybridizes to the sequence contained in exon 1 from VAPB or the sequence located at 5' of exon 1, and / or the sequence contained in exon 2 from NRG1 or the sequence located at 3' of exon 2, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of CADM1 and NRG1 specifically hybridizes to the sequence contained in exon 7 from CADM1 or the sequence located at 5' of exon 7, and / or the sequence contained in exon 6 from NRG1 or the sequence located at 3' of exon 6, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of CD44 and NRG1 specifically hybridizes to the sequence contained in exon 5 from CD44 or the sequence located at 5' of exon 5, and / or the sequence contained in exon 2 from NRG1 or the sequence located at 3' of exon 2, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of the transcription version 6 of SLC3A2 and NRG1 specifically hybridizes to the sequence contained in exon 1 from SLC3A2 or the sequence located at 5' of exon 1, and / or the sequence contained in exon 5 from NRG1 or the sequence located at 3' of exon 5, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of VTCN1 and NRG1 specifically hybridizes to a sequence contained in exon 2 from VTCN1 or a sequence located at 5' of exon 2, and / or a sequence contained in exon 2 from NRG1 or a sequence located at 3' of exon 2, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of CDH1 and NRG1 specifically hybridizes to a sequence contained in exon 11 from CDH1 or a sequence located at 5' of exon 11, and / or a sequence contained in exon 2 from NRG1 or a sequence located at 3' of exon 2, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of CXADR and NRG1 specifically hybridizes to a sequence contained in exon 1 from CXADR or a sequence located at 5' of exon 1, and / or a sequence contained in exon 2 from NRG1 or a sequence located at 3' of exon 2, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of GTF2E2 and NRG1 specifically hybridizes to a sequence contained in exon 2 from GTF2E2 or a sequence located at 5' of exon 2, and / or a sequence contained in exon 2 from NRG1 or a sequence located at 3' of exon 2, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of CSMD1 and NRG1 specifically hybridizes to the sequence contained in exon 23 from CSMD1 or the sequence located at 5' of exon 23, and / or the sequence contained in exon 6 from NRG1 or the sequence located at 3' of exon 6, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of PTN and NRG1 specifically hybridizes to the sequence contained in exon 4 from PTN or the sequence located at 5' of exon 4, and / or the sequence contained in exon 2 from NRG1 or the sequence located at 3' of exon 2, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of ST14 and NRG1 specifically hybridizes to the sequence contained in exon 11 from ST14 or the sequence located at 5' of exon 11, and / or the sequence contained in exon 6 from NRG1 or the sequence located at 3' of exon 6, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of THBS1 and NRG1 specifically hybridizes to the sequence contained in exon 9 from THBS1 or the sequence located at 5' of exon 9, and / or the sequence contained in exon 6 from NRG1 or the sequence located at 3' of exon 6, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of AGRN and NRG1 specifically hybridizes to the sequence contained in exon 12 from AGRN or the sequence located at 5' of exon 12, and / or the sequence contained in exon 6 from NRG1 or the sequence located at 3' of exon 6, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of PVALB and NRG1 specifically hybridizes to the sequence contained in exon 4 from PVALB or the sequence located at 5' of exon 4, and / or the sequence contained in exon 6 from NRG1 or the sequence located at 3' of exon 6, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of the transcription version 3 of SLC3A2 and NRG1 specifically hybridizes to the sequence contained in exon 2 from SLC3A2 or the sequence located at 5' of exon 2, and / or the sequence contained in exon 6 from NRG1 or the sequence located at 3' of exon 6, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of APP and NRG1 specifically hybridizes to the sequence contained in exon 14 from APP or the sequence located at 5' of exon 14, and / or the sequence contained in exon 6 from NRG1 or the sequence located at 3' of exon 6, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of WRN and NRG1 specifically hybridizes to the sequence contained in exon 33 from WRN or the sequence located at 5' of exon 33, and / or the sequence contained in exon 6 from NRG1 or the sequence located at 3' of exon 6, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of DAAM1 and NRG1 specifically hybridizes to a sequence contained in exon 1 from DAAM1 or a sequence located at 5' of exon 1, and / or a sequence contained in exon 1 from NRG1 or a sequence located at 3' of exon 1, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of ASPH and NRG1 specifically hybridizes to a sequence contained in exon 22 from ASPH or a sequence located at 5' of exon 22, and / or a sequence contained in exon 2 from NRG1 or a sequence located at 3' of exon 2, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of NOTCH2 and NRG1 specifically hybridizes to the sequence contained in exon 6 from NOTCH2 or the sequence located at 5' of exon 6, and / or the sequence contained in exon 6 from NRG1 or the sequence located at 3' of exon 6, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of CD74 and NRG1 specifically hybridizes to the sequence contained in exon 2 from CD74 or the sequence located at 5' of exon 2, and / or the sequence contained in exon 2 from NRG1 or the sequence located at 3' of exon 2, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of SDC4 and NRG1 specifically hybridizes to a sequence contained in exon 2 from SDC4 or a sequence located at 5' of exon 2, and / or a sequence contained in exon 2 from NRG1 or a sequence located at 3' of exon 2, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of CD44 and NRG1 specifically hybridizes to the sequence contained in exon 5 from CD44 or the sequence located at 5' of exon 5, and / or the sequence contained in exon 6 from NRG1 or the sequence located at 3' of exon 6, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of SLC4A4 and NRG1 specifically hybridizes to the sequence contained in exon 14 from SLC4A4 or the sequence located at 5' of exon 14, and / or the sequence contained in exon 6 from NRG1 or the sequence located at 3' of exon 6, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of SDC4 and NRG1 specifically hybridizes to the sequence contained in exon 4 from SDC4 or the sequence located at 5' of exon 4, and / or the sequence contained in exon 2 from NRG1 or the sequence located at 3' of exon 2, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of ZFAT and NRG1 specifically hybridizes to the sequence contained in exon 12 from ZFAT or the sequence located at 5' of exon 12, and / or the sequence contained in exon 6 from NRG1 or the sequence located at 3' of exon 6, or has 95% or more complementary sequence identity with it, or - A nucleic acid probe, primer, or primer pair according to any one of claims 24 to 26, wherein the probe, primer, or primer pair for detecting the fusion of DSCAM1 and NRG1 specifically hybridizes to a sequence contained in exon 3 from DSCAM1 or a sequence located at 5' of exon 3, and / or a sequence contained in exon 2 from NRG1 or a sequence located at 3' of exon 2, or has 95% or more complementary sequence identity with it.

28. - Exon 1 from VAPB contains or consists of SEQ ID NO: 17 or its allele variant. - Exon 7 from CADM1 contains or consists of SEQ ID NO: 39 or its allele variant, - Exon 5 from CD44 contains or consists of SEQ ID NO: 65 or its allele variant, - Exon 1 from SLC3A2 contains or consists of SEQ ID NO: 103 or its allele variant. - Exon 2 from VTCN1 contains or consists of SEQ ID NO: 169 or its allele variant, - Exon 11 from CDH1 contains or consists of SEQ ID NO: 198 or its allele variant, - Exon 1 from CXADR contains or consists of SEQ ID NO: 219 or its allele variant, - Exon 2 from GTF2E2 contains or consists of SEQ ID NO: 236 or its allele variant. - Exon 23 from CSMD1 contains or consists of SEQ ID NO: 279 or its allele variant, - Exon 4 from PTN contains or consists of SEQ ID NO: 318 or its allele variant. - Exon 11 from ST14 contains or consists of SEQ ID NO: 342 or its allele variant. - Exon 9 from THBS1 contains or consists of SEQ ID NO: 386 or its allele variant, - Exon 12 from AGRN contains or consists of SEQ ID NO: 416 or its allele variant, - Exon 4 from PVALB contains or consists of SEQ ID NO: 442 or its allele variant. - Exon 2 from SLC3A2 contains or consists of SEQ ID NO: 457 or its allele variant. - Exon 14 from APP contains or consists of SEQ ID NO: 501 or its allele variant. - Exon 33 from WRN contains or consists of SEQ ID NO: 562 or its allele variant. - Exon 1 from DAAM1 contains or consists of SEQ ID NO: 606 or its allele variant, - Exon 22 from ASPH contains or consists of SEQ ID NO: 658 or its allele variant, - Exon 6 from NOTCH2 contains or consists of SEQ ID NO: 700 or its allele variant. - Exon 2 from CD74 contains or consists of SEQ ID NO: 720 or its allele variant, - Exon 2 from SDC4 contains or consists of SEQ ID NO: 746 or its allele variant. - Exon 5 from CD44 contains or consists of SEQ ID NO: 65 or its allele variant, - Exon 14 from SLC4A4 contains or consists of SEQ ID NO: 780 or its allele variant. - Exon 4 from SDC4 contains or consists of SEQ ID NO: 748 or its allele variant. - Exon 12 from ZFAT contains or consists of SEQ ID NO: 841 or its allele variant. - Exon 3 from DSCAM1 contains or consists of SEQ ID NO: 872 or its allele variant, and - The nucleic acid probe, primer, or primer pair according to claim 27, wherein exons 1, 2, 5, and 6 from NRG1 each include or consist of sequence numbers 125, 126, 129, and 130 or their allele variants.

29. - The probe, primer, or primer pair for detecting the fusion of VAPB and NRG1 specifically hybridizes with the sequence contained in SEQ ID NO: 17 or its allele variant, and / or the sequence contained in SEQ ID NO: 153, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of CADM1 and NRG1 specifically hybridizes with the sequence included by SEQ ID NO: 57 and / or the sequence included by SEQ ID NO: 155, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of CD44 and NRG1 specifically hybridizes with the sequence included by SEQ ID NO: 99 and / or the sequence included by SEQ ID NO: 153, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of SLC3A2 and NRG1 specifically hybridizes with the sequence included by SEQ ID NO: 103 and / or the sequence included by SEQ ID NO: 157, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of VTCN1 and NRG1 specifically hybridizes with the sequence included by SEQ ID NO: 181 and / or the sequence included by SEQ ID NO: 153, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of CDH1 and NRG1 specifically hybridizes with the sequence included by SEQ ID NO: 213 and / or the sequence included by SEQ ID NO: 153, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of CXADR and NRG1 specifically hybridizes with the sequence included by SEQ ID NO: 219 and / or the sequence included by SEQ ID NO: 153, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of GTF2E2 and NRG1 specifically hybridizes with the sequence included by SEQ ID NO: 252 and / or the sequence included by SEQ ID NO: 153, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of CSMD1 and NRG1 specifically hybridizes with the sequence included by SEQ ID NO: 309 and / or the sequence included by SEQ ID NO: 155, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of PTN and NRG1 specifically hybridizes with the sequence included by SEQ ID NO: 326 and / or the sequence included by SEQ ID NO: 153, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of ST14 and NRG1 specifically hybridizes with the sequence included by SEQ ID NO: 372 and / or the sequence included by SEQ ID NO: 155, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of THBS1 and NRG1 specifically hybridizes with the sequence included by SEQ ID NO: 399 and / or the sequence included by SEQ ID NO: 155, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of AGRN and NRG1 specifically hybridizes with the sequence included by SEQ ID NO: 433 and / or the sequence included by SEQ ID NO: 155, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of PVALB and NRG1 specifically hybridizes with the sequence included by SEQ ID NO: 450 and / or the sequence included by SEQ ID NO: 155, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of SLC3A2 and NRG1 specifically hybridizes with the sequence included by SEQ ID NO: 482 and / or the sequence included by SEQ ID NO: 155, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of APP and NRG1 specifically hybridizes with the sequence included by SEQ ID NO: 524 and / or the sequence included by SEQ ID NO: 155, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of WRN and NRG1 specifically hybridizes with the sequence included by SEQ ID NO: 601 and / or the sequence included by SEQ ID NO: 155, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of DAAM1 and NRG1 specifically hybridizes with the sequence included by SEQ ID NO: 606 and / or the sequence included by SEQ ID NO: 138, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of ASPH and NRG1 specifically hybridizes with the sequence included by SEQ ID NO: 689 and / or the sequence included by SEQ ID NO: 153, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of NOTCH2 and NRG1 specifically hybridizes with the sequence included by SEQ ID NO: 713 and / or the sequence included by SEQ ID NO: 155, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of CD74 and NRG1 specifically hybridizes with the sequence included by SEQ ID NO: 739 and / or the sequence included by SEQ ID NO: 153, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of SDC4 and NRG1 specifically hybridizes with the sequence included by SEQ ID NO: 757 and / or the sequence included by SEQ ID NO: 153, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of CD44 and NRG1 specifically hybridizes with the sequence included by SEQ ID NO: 99 and / or the sequence included by SEQ ID NO: 155, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of SLC4A4 and NRG1 specifically hybridizes with the sequence included by SEQ ID NO: 820 and / or the sequence included by SEQ ID NO: 155, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of SDC4 and NRG1 specifically hybridizes with the sequence included by SEQ ID NO: 940 and / or the sequence included by SEQ ID NO: 153, or has 95% or more complementary sequence identity with it. - The probe, primer, or primer pair for detecting the fusion of ZFAT and NRG1 specifically hybridizes with the sequence included by SEQ ID NO: 864 and / or the sequence included by SEQ ID NO: 155, or has 95% or more complementary sequence identity with it, and - The nucleic acid probe, primer, or primer pair according to claim 27, wherein the probe, primer, or primer pair for detecting the fusion of DSCAML1 and NRG1 specifically hybridizes with the sequence contained by SEQ ID NO: 938 and / or the sequence contained by SEQ ID NO: 153, or has 95% or more complementary sequence identity with it.

30. A first and second nucleic acid probe for use in an in situ hybridization assay for detecting a polynucleotide fusion according to any one of claims 1 to 17, - The first probe specifically hybridizes to the VAPB sequence located at 5' from the nucleic acid at position 43 of SEQ ID NO: 3, and the second probe specifically hybridizes to the NRG1 sequence located at 3' from the nucleic acid at position 44 of SEQ ID NO:

3. - The first probe specifically hybridizes to the CADM1 sequence located at 5' from the nucleic acid at position 53 of SEQ ID NO: 7, and the second probe specifically hybridizes to the NRG1 sequence located at 3' from the nucleic acid at position 54 of SEQ ID NO:

7. - The first probe specifically hybridizes to the CD44 sequence located at 5' from the nucleic acid at position 52 of SEQ ID NO: 11, and the second probe specifically hybridizes to the NRG1 sequence located at 3' from the nucleic acid at position 53 of SEQ ID NO:

11. - The first probe specifically hybridizes to the SLC3A2 sequence located at 5' from the nucleic acid at position 53 of SEQ ID NO: 15, and the second probe specifically hybridizes to the NRG1 sequence located at 3' from the nucleic acid at position 54 of SEQ ID NO:

15. - The first probe specifically hybridizes to the VTCN1 sequence located at 5' from the nucleic acid at position 65 of SEQ ID NO: 166, and the second probe specifically hybridizes to the NRG1 sequence located at 3' from the nucleic acid at position 66 of SEQ ID NO:

166. - The first probe specifically hybridizes to the CDH1 sequence located at 5' from the nucleic acid at position 119 of SEQ ID NO: 186, and the second probe specifically hybridizes to the NRG1 sequence located at 3' from the nucleic acid at position 120 of SEQ ID NO:

186. - The first probe specifically hybridizes to the CXADR sequence located at 5' from the nucleic acid at position 43 of SEQ ID NO: 217, and the second probe specifically hybridizes to the NRG1 sequence located at 3' from the nucleic acid at position 44 of SEQ ID NO:

217. - The first probe specifically hybridizes to the GTF2E2 sequence located at 5' from the nucleic acid at position 141 of SEQ ID NO: 233, and the second probe specifically hybridizes to the NRG1 sequence located at 3' from the nucleic acid at position 142 of SEQ ID NO:

233. - The first probe specifically hybridizes to the CSMD1 sequence located at 5' from the nucleic acid at position 88 of SEQ ID NO: 255, and the second probe specifically hybridizes to the NRG1 sequence located at 3' from the nucleic acid at position 89 of SEQ ID NO:

255. - The first probe specifically hybridizes to the PTN sequence located at 5' from the nucleic acid at position 102 of sequence number 313, and the second probe specifically hybridizes to the NRG1 sequence located at 3' from the nucleic acid at position 103 of sequence number 313. - The first probe specifically hybridizes to the ST14 sequence located at 5' from the nucleic acid at position 95 of SEQ ID NO: 330, and the second probe specifically hybridizes to the NRG1 sequence located at 3' from the nucleic acid at position 96 of SEQ ID NO:

330. - The first probe specifically hybridizes to the THBS1 sequence located at 5' from the nucleic acid at position 56 of sequence number 376, and the second probe specifically hybridizes to the NRG1 sequence located at 3' from the nucleic acid at position 57 of sequence number 376. - The first probe specifically hybridizes to the AGRN sequence located at 5' from the nucleic acid at position 106 of sequence number 403, and the second probe specifically hybridizes to the NRG1 sequence located at 3' from the nucleic acid at position 107 of sequence number 403. - The first probe specifically hybridizes to the PVALB sequence located at 5' from the nucleic acid at position 102 of SEQ ID NO: 437, and the second probe specifically hybridizes to the NRG1 sequence located at 3' from the nucleic acid at position 103 of SEQ ID NO:

437. - The first probe specifically hybridizes to the SLC3A2 sequence located at 5' from the nucleic acid at position 93 of SEQ ID NO: 454, and the second probe specifically hybridizes to the NRG1 sequence located at 3' from the nucleic acid at position 94 of SEQ ID NO:

454. - The first probe specifically hybridizes to the APP sequence located at 5' from the nucleic acid at position 54 of sequence number 486, and the second probe specifically hybridizes to the NRG1 sequence located at 3' from the nucleic acid at position 55 of sequence number 486. - The first probe specifically hybridizes to the WRN sequence located at 5' from the nucleic acid at position 96 of SEQ ID NO: 528, and the second probe specifically hybridizes to the NRG1 sequence located at 3' from the nucleic acid at position 97 of SEQ ID NO:

528. - The first probe specifically hybridizes to the DAAM1 sequence located at 5' from the nucleic acid at position 75 of SEQ ID NO: 605, and the second probe specifically hybridizes to the NRG1 sequence located at 3' from the nucleic acid at position 76 of SEQ ID NO:

605. - The first probe specifically hybridizes to the ASPH sequence located at 5' from the nucleic acid at position 75 of SEQ ID NO: 635, and the second probe specifically hybridizes to the NRG1 sequence located at 3' from the nucleic acid at position 76 of SEQ ID NO:

635. - The first probe specifically hybridizes to the NOTCH2 sequence located at 5' from the nucleic acid at position 75 of SEQ ID NO: 693, and the second probe specifically hybridizes to the NRG1 sequence located at 3' from the nucleic acid at position 76 of SEQ ID NO:

693. - The first probe specifically hybridizes to the CD74 sequence located at 5' from the nucleic acid at position 75 of sequence number 717, and the second probe specifically hybridizes to the NRG1 sequence located at 3' from the nucleic acid at position 76 of sequence number 717. - The first probe specifically hybridizes to the SDC4 sequence located at 5' from the nucleic acid at position 75 of SEQ ID NO: 743, and the second probe specifically hybridizes to the NRG1 sequence located at 3' from the nucleic acid at position 76 of SEQ ID NO:

743. - The first probe specifically hybridizes to the CD44 sequence located at 5' from the nucleic acid at position 75 of sequence number 761, and the second probe specifically hybridizes to the NRG1 sequence located at 3' from the nucleic acid at position 76 of sequence number 761. - The first probe specifically hybridizes to the SLC4A4 sequence located at 5' from the nucleic acid at position 75 of SEQ ID NO: 765, and the second probe specifically hybridizes to the NRG1 sequence located at 3' from the nucleic acid at position 76 of SEQ ID NO:

765. - The first probe specifically hybridizes to the SDC4 sequence located at 5' from the nucleic acid at position 75 of SEQ ID NO: 824, and the second probe specifically hybridizes to the NRG1 sequence located at 3' from the nucleic acid at position 76 of SEQ ID NO:

824. - The first probe specifically hybridizes to the ZFAT sequence located at 5' from the nucleic acid at position 75 of SEQ ID NO: 828, and the second probe specifically hybridizes to the NRG1 sequence located at 3' from the nucleic acid at position 76 of SEQ ID NO: 828, or - First and second nucleic acid probes, wherein the first probe specifically hybridizes to the DSCAM1 sequence located 5' from the nucleic acid at position 75 of sequence number 868, and the second probe specifically hybridizes to the NRG1 sequence located 3' from the nucleic acid at position 76 of sequence number 868.

31. A first antibody, or a set of first and second antibody pairs, for detecting a polypeptide encoded by a polynucleotide fusion according to any one of claims 1 to 17.

32. A detection assay comprising a first antibody or a set of first and second antibodies for detecting the presence of a polypeptide encoded by a polynucleotide fusion according to any one of claims 1 to 17, wherein the first antibody or the set of first and second antibodies is preferably the first antibody or the set of first and second antibodies according to claim 31.

33. The first antibody is VAPB-NRG1, CADM1-NRG1, CD44-NRG1, SLC3A2-NRG1, VTCN1-NRG1, CDH1-NRG1, CXADR-NRG1, GTF2E2-NRG1, CSMD1-NRG1, PTN-NRG1, ST14-NRG1, THBS1-NRG1, AGRN-NRG1, PVALB-NR The first and second antibody sets are conjugated to polypeptide fusions selected from G1, APP-NRG1, WRN-NRG1, ASPH-NRG1, NOTCH2-NRG1, CD74-NRG1, SDC4-NRG1, SLC4A4-NRG1, ZFAT-NRG1, or DSCAML1-NRG1, and the sets of the first and second antibodies are conjugated to VAPB and NRG1 or CADM, respectively. 1 and NRG1, or CD44 and NRG1, SLC3A2 and NRG1, VTCN1 and NRG1, CDH1 and NRG1, CXADR and NRG1, GTF2E2 and NRG1, CSMD1 and NRG1, PTN and NRG1, ST14 and NRG1, THBS1 and NRG1, AGRN and NRG1, PVALB and NRG1, APP and A first antibody or a set of first and second antibodies according to claim 31, which binds to NRG1, WRN and NRG1, ASPH and NRG1, NOTCH2 and NRG1, CD74 and NRG1, SDC4 and NRG1, SLC4A4 and NRG1, ZFAT and NRG1, or DSCAML1 and NRG1, or a detection assay according to claim 32.

34. A method for identifying a polynucleotide fusion according to any one of claims 1 to 17, or a polypeptide encoded therefrom, in a sample, comprising testing a sample obtained from a subject to detect the presence of the fusion in the sample.

35. A method for detecting the presence of a polynucleotide fusion according to any one of claims 1 to 17, or a polypeptide encoded therefrom, in a sample, comprising testing a sample obtained from a subject to detect the presence of the fusion in the sample.

36. A method for determining whether abnormal cells derived from a subject contain a polynucleotide fusion described in any one of claims 1 to 17, or a polypeptide encoded therefrom, the method comprising testing the polynucleotide or polypeptide-containing components of the abnormal cells obtained from the subject for the presence of the fusion in the sample.

37. A method for identifying a subject having a polynucleotide fusion according to any one of claims 1 to 17, or a polypeptide encoded therefrom, comprising testing a sample obtained from the subject to detect the presence of the fusion in the sample.

38. The method according to any one of claims 34 to 37, wherein the test includes detecting the fusion by using a binder that specifically binds to the polynucleotide, for example, a nucleic acid probe, primer or primer pair described in claims 24 to 29, or a polypeptide encoded thereby, or by using a binder that binds to a polynucleotide containing the polynucleotide fusion.

39. The method according to any one of claims 34 to 38, wherein the test comprises amplifying or detecting a sequence that distinguishes the presence or absence of the polynucleotide fusion or polypeptide encoded therefrom.

40. The method according to any one of claims 34 to 39, wherein the polynucleotide fusion is obtained from abnormal cells expressing a polynucleotide fusion containing the EGF-like domain of NRG1.

41. The method according to any one of claims 34 to 40, comprising the steps of obtaining the sample from a subject, and subsequently isolating the polynucleotide or a polypeptide encoded therefrom from the sample.

42. The method according to any one of claims 34 to 41, comprising the step of purifying or isolating the polynucleotide or polypeptide from the sample.

43. The method according to any one of claims 34 to 42, wherein the binder is a primer, a primer pair, a probe, or an antibody, or comprises the same.

44. The method according to any one of claims 34 to 43, wherein the test is an ex vivo method, preferably an in vitro method.

45. The method according to any one of claims 34 to 44, wherein the binder comprises or associates with a detectable label.

46. The method according to any one of claims 34 to 45, wherein the sample is a liquid biopsy sample such as a formalin-fixed paraffin-embedded tissue (FFPE) sample or a solid sample.

47. The method according to any one of claims 34 to 46, wherein the sample comprises blood, serum, plasma, pleural fluid, urine, semen, amniotic fluid, or peritoneal fluid.

48. The method according to any one of claims 34 to 47, wherein the sample comprises abnormal cells such as tumor cells or cancer cells, or a polynucleotide or polypeptide-containing substance thereof.

49. A method for treating a subject having ErbB-2 and / or ErbB-3 positive cancer or tumor that expresses a polynucleotide fusion and / or a fusion polypeptide encoded therefrom, comprising administering to the subject an effective amount of an ErbB-2 and / or ErbB-3 targeting agent, wherein the fusion is the fusion according to any one of claims 1 to 17.

50. A method for inhibiting the progression of an ErbB-2 and ErbB-3 positive cancer or tumor subject expressing a polynucleotide fusion and / or a fusion polypeptide encoded therefrom, comprising administering to the subject an effective amount of an ErbB-2 and / or ErbB-3 targeting agent, wherein the fusion is the fusion according to any one of claims 1 to 17.

51. An ErbB-2 and / or ErbB-3 targeting agent for use in the treatment of a subject having ErbB-2 and ErbB-3 positive cancer or tumor, which expresses a fusion polypeptide comprising and / or encoded thereof, wherein the treatment comprises administering to the subject an effective amount of the ErbB-2 and / or ErbB-3 targeting agent, the fusion being the fusion according to any one of claims 1 to 17.

52. A method for diagnosing a subject with respect to abnormal cells comprising a polynucleotide fusion according to any one of claims 1 to 17, or a polypeptide encoded therefrom, the method comprising testing a sample obtained from the subject to detect the presence of the fusion in the sample.

53. The method according to claim 52, wherein the test includes detecting the fusion by using a binder that specifically binds to the polynucleotide, for example, a nucleic acid probe, primer or primer pair described in any one of claims 24 to 29, or a polypeptide encoded therefrom, or by using a binder that binds to a polynucleotide containing the polynucleotide fusion.

54. A method for evaluating whether a subject is suffering from cancer or a tumor, or is susceptible to cancer or a tumor, comprising: testing a sample obtained from the subject to detect the presence of a polynucleotide fusion described in any one of claims 1 to 17, or a polypeptide encoded therefrom, in the sample; and evaluating whether the subject is suffering from cancer or a tumor, or is susceptible to cancer or a tumor, by identifying the presence of the polynucleotide or polypeptide fusion.

55. The method or use according to any one of claims 49 to 51, wherein the ErbB-2 and / or ErbB-3 targeting agent is selected from the group consisting of a multispecific antibody comprising a first antigen-binding site that binds to the extracellular space of ErbB-2 and a second antigen-binding site that binds to the extracellular space of ErbB-3, an ErbB-2 tyrosine kinase inhibitor, a monospecific bivalent antibody comprising an antigen-binding site that binds to the extracellular space of ErbB-2, a monospecific bivalent antibody comprising an antigen-binding site that binds to the extracellular space of ErbB-3, or any combination thereof.

56. The method or use according to any one of claims 49 to 51 or 55, wherein the ErbB-2 and / or ErbB-3 targeting agent is xenoctuzumab.

57. The method or use according to any one of claims 35 to 56, wherein the abnormal cells, cancer cells, tumor cells, or sample comprises a polynucleotide fusion according to claims 1 to 17, or a polypeptide encoded thereby, and the polynucleotide fusion contained by the cell or sample further comprises an intraframe fusion of a coding sequence encoding the EGF-like domain of NRG1.

58. The method or use according to any one of claims 35 to 57, wherein the abnormal cells are from cancer, and in particular the cancer is adenocarcinoma, more specifically mucinous adenocarcinoma, pancreatic cancer, particularly pancreatic adenocarcinoma, more specifically pancreatic ductal adenocarcinoma, renal cell carcinoma, sarcoma, bladder, colon, rectum, colorectal, gallbladder, head and neck cancer, prostate, uterus, breast cancer, ovarian cancer, liver cancer, endometrial cancer, lung cancer, preferably non-small cell lung cancer, preferably more preferably invasive mucinous adenocarcinoma, or primary or metastatic cancer.

59. An in vivo animal model expressing a polynucleotide fusion and / or a polypeptide fusion encoded therefrom, wherein the polynucleotide fusion or polypeptide fusion contained by the animal model is contained by abnormally engrafted cells present in the animal model or by the genome of the animal model.

60. A method for treating an in vivo animal model according to claim 59 with an Erb2 and / or Erb3 targeting agent selected from the group consisting of a multispecific antibody comprising a first antigen-binding site that binds to the extracellular space of ErbB-2 and a second antigen-binding site that binds to the extracellular space of ErbB-3, an ErbB-2 tyrosine kinase inhibitor, a monospecific bivalent antibody comprising an antigen-binding site that binds to the extracellular space of ErbB-2, a monospecific bivalent antibody comprising an antigen-binding site that binds to the extracellular space of ErbB-3, or any combination thereof, the method comprising administering the Erb2 and / or Erb3 targeting agent to the animal.

61. First and second nucleic acid probes for use in an in situ hybridization assay to detect gene rearrangements of VAPB, CADM1, CD44, SLC3A2, VTCN1, CDH1, CXADR, GTF2E2, CSMD1, PTN, ST14, THBS1, AGRN, PVALB, APP, WRN, DAAM1, ASPH, NOTCH2, CD74, SDC4, SLC4A4, ZFAT, or DSCAML1, - The first probe for detecting VAPB gene rearrangement specifically hybridizes from the nucleic acid at position 43 of SEQ ID NO: 1 to the VAPB sequence at 5', and the second probe specifically hybridizes from the nucleic acid at position 43 of SEQ ID NO: 1 to the VAPB sequence at 3'. - The first probe for detecting the CADM1 gene rearrangement specifically hybridizes the CADM1 sequence located at 5' from the nucleic acid at position 53 of SEQ ID NO: 5, and the second probe specifically hybridizes the CADM1 sequence located at 3' from the nucleic acid at position 53 of SEQ ID NO:

5. - The first probe for detecting CD44 gene rearrangements specifically hybridizes the nucleic acid at position 52 of SEQ ID NO: 9 to the CD44 sequence at 5', and the second probe specifically hybridizes the nucleic acid at position 52 of SEQ ID NO: 9 to the CD44 sequence at 3'. - The first probe for detecting SLC3A2 gene rearrangement specifically hybridizes from the nucleic acid at position 53 of SEQ ID NO: 13 to the SLC3A2 sequence at 5', and the second probe specifically hybridizes from the nucleic acid at position 53 of SEQ ID NO: 13 to the SLC3A2 sequence at 3'. - The first probe for detecting VTCN1 gene rearrangement specifically hybridizes the nucleic acid at position 65 of SEQ ID NO: 164 to the VTCN1 sequence at 5', and the second probe specifically hybridizes the nucleic acid at position 65 of SEQ ID NO: 164 to the VTCN1 sequence at 3'. - The first probe for detecting CDH1 gene rearrangement specifically hybridizes the nucleic acid at position 119 of SEQ ID NO: 184 to the CDH1 sequence at 5', and the second probe specifically hybridizes the nucleic acid at position 119 of SEQ ID NO: 184 to the CDH1 sequence at 3'. - The first probe for detecting CXADR gene rearrangements specifically hybridizes the nucleic acid at position 43 of SEQ ID NO: 215 to the CXADR sequence at 5', and the second probe specifically hybridizes the nucleic acid at position 43 of SEQ ID NO: 215 to the CXADR sequence at 3'. - The first probe for detecting the GTF2E2 gene rearrangement specifically hybridizes the nucleic acid at position 141 of SEQ ID NO: 231 to the GTF2E2 sequence at 5', and the second probe specifically hybridizes the nucleic acid at position 141 of SEQ ID NO: 231 to the GTF2E2 sequence at 3'. - The first probe for detecting CSMD1 gene rearrangement specifically hybridizes the nucleic acid at position 88 of SEQ ID NO: 253 to the CSMD1 sequence at 5', and the second probe specifically hybridizes the nucleic acid at position 88 of SEQ ID NO: 253 to the CSMD1 sequence at 3'. - The first probe for detecting PTN gene rearrangements specifically hybridizes the nucleic acid at position 102 of SEQ ID NO: 311 to the PTN sequence at 5', and the second probe specifically hybridizes the nucleic acid at position 102 of SEQ ID NO: 311 to the PTN sequence at 3'. - The first probe for detecting ST14 gene rearrangement specifically hybridizes the ST14 sequence located at 5' from the nucleic acid at position 95 of SEQ ID NO: 328, and the second probe specifically hybridizes the ST14 sequence located at 3' from the nucleic acid at position 95 of SEQ ID NO:

328. - The first probe for detecting AGRN gene rearrangements specifically hybridizes the nucleic acid at position 106 of SEQ ID NO: 401 to the AGRN sequence at 5', and the second probe specifically hybridizes the nucleic acid at position 106 of SEQ ID NO: 401 to the AGRN sequence at 3'. - The first probe for detecting THBS1 gene rearrangement specifically hybridizes the nucleic acid at position 56 of SEQ ID NO: 374 to the THBS1 sequence at 5', and the second probe specifically hybridizes the nucleic acid at position 56 of SEQ ID NO: 374 to the THBS1 sequence at 3'. - The first probe for detecting PVALB gene rearrangements specifically hybridizes the nucleic acid at position 102 of SEQ ID NO: 435 to the PVALB sequence at 5', and the second probe specifically hybridizes the nucleic acid at position 102 of SEQ ID NO: 435 to the PVALB sequence at 3'. - The first probe for detecting SLC3A2 gene rearrangement specifically hybridizes from the nucleic acid at position 93 of SEQ ID NO: 452 to the SLC3A2 sequence at 5', and the second probe specifically hybridizes from the nucleic acid at position 93 of SEQ ID NO: 452 to the SLC3A2 sequence at 3', - The first probe for detecting APP gene rearrangements specifically hybridizes the nucleic acid at position 54 of SEQ ID NO: 484 to the APP sequence at 5', and the second probe specifically hybridizes the nucleic acid at position 54 of SEQ ID NO: 484 to the APP sequence at 3'. - The first probe for detecting WRN gene rearrangements specifically hybridizes from the nucleic acid at position 96 of SEQ ID NO: 526 to the WRN sequence at 5', and the second probe specifically hybridizes from the nucleic acid at position 96 of SEQ ID NO: 526 to the WRN sequence at 3'. - The first probe for detecting DAAM1 gene rearrangement specifically hybridizes the DAAM1 sequence located at 5' from the nucleic acid at position 75 of SEQ ID NO: 603, and the second probe specifically hybridizes the DAAM1 sequence located at 3' from the nucleic acid at position 75 of SEQ ID NO:

603. - The first probe for detecting ASPH gene rearrangement specifically hybridizes from the nucleic acid at position 75 of SEQ ID NO: 633 to the ASPH sequence at 5', and the second probe specifically hybridizes from the nucleic acid at position 75 of SEQ ID NO: 633 to the ASPH sequence at 3', - The first probe for detecting NOTCH2 gene rearrangement specifically hybridizes from the nucleic acid at position 75 of SEQ ID NO: 691 to the NOTCH2 sequence at 5', and the second probe specifically hybridizes from the nucleic acid at position 75 of SEQ ID NO: 691 to the NOTCH2 sequence at 3', - The first probe for detecting CD74 gene rearrangements specifically hybridizes the nucleic acid at position 75 of SEQ ID NO: 715 to the CD74 sequence at 5', and the second probe specifically hybridizes the nucleic acid at position 75 of SEQ ID NO: 715 to the CD74 sequence at 3'. - The first probe for detecting SDC4 gene rearrangement specifically hybridizes from the nucleic acid at position 75 of SEQ ID NO: 741 to the SDC4 sequence at 5', and the second probe specifically hybridizes from the nucleic acid at position 75 of SEQ ID NO: 741 to the SDC4 sequence at 3'. - The first probe for detecting CD44 gene rearrangements specifically hybridizes the nucleic acid at position 75 of SEQ ID NO: 759 to the CD44 sequence at 5', and the second probe specifically hybridizes the nucleic acid at position 75 of SEQ ID NO: 759 to the CD44 sequence at 3'. - The first probe for detecting SLC4A4 gene rearrangement specifically hybridizes from the nucleic acid at position 75 of SEQ ID NO: 763 to the SLC4A4 sequence at 5', and the second probe specifically hybridizes from the nucleic acid at position 75 of SEQ ID NO: 763 to the SLC4A4 sequence at 3'. - The first probe for detecting SDC4 gene rearrangement specifically hybridizes from the nucleic acid at position 75 of SEQ ID NO: 822 to the SDC4 sequence at 5', and the second probe specifically hybridizes from the nucleic acid at position 75 of SEQ ID NO: 822 to the SDC4 sequence at 3', - The first probe for detecting ZFAT gene rearrangements specifically hybridizes to the ZFAT sequence located at 5' from the nucleic acid at position 75 of SEQ ID NO: 826, and the second probe specifically hybridizes to the ZFAT sequence located at 3' from the nucleic acid at position 75 of SEQ ID NO: 826, or - First and second nucleic acid probes for detecting DSCAML1 gene rearrangements, wherein the first probe specifically hybridizes to the DSCAML1 sequence located at 5' from the nucleic acid at position 75 of SEQ ID NO: 866, and the second probe specifically hybridizes to the DSCAML1 sequence located at 3' from the nucleic acid at position 75 of SEQ ID NO: 866.

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