New nrg1 fusions, fusion junctions and methods for detecting them

Abstract

This disclosure relates to the field of neuroregulatory protein 1 (NRG1) fusions, methods for detecting such fusions, methods for identifying or diagnosing patients with such fusions, and methods for treating cancers, tumors, or abnormal cells containing NRG1 fusions. Furthermore, this disclosure relates to the field of therapeutic (human) antibodies for treating individuals with ErbB-2 / ErbB-3 positive cancers containing NRG1 fusions.

Description

[Technical Field]

[0001] This disclosure relates to the field of neuroregulatory protein 1 (NRG1) fusions, methods for detecting such fusions, methods for identifying or diagnosing patients with such fusions, and methods for treating cancers, tumors, or abnormal cells containing NRG1 fusions. Furthermore, this disclosure relates to the field of therapeutic (human) antibodies for treating individuals with ErbB-2 / ErbB-3 positive cancers containing NRG1 fusions. [Previous Technology]

[0003] The degradation 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, which is necessary for direct binding to receptor tyrosine kinases ErbB-3 and ErbB-4. The NRG1 gene and its isoforms are known by many different names, such as: Neuregulin 1; Pro-NRG1; HRGA; SMDF; HGL; GGF; NDF; NRG1 Intronic Transcript 2 (not encoding a protein); Heregulin, α (45kD, ERBB2 P185 activator); Acetylcholine Receptor-Inducing Activity; Pro-Neuregulin-1 (a membrane-bound isoform); Sensory and Motor Neuron Derivative Factor; Neu Differentiation Factor; Glial Growth Factor 2; NRG1-IT2; MSTP131; MST131; ARIA; GGF2; HRG1; and HRG. The external IDs of the NRG1 gene are HGNC: 7997; Entrez Gene: 3084; Ensembl: ENSG00000157168; OMIM: 142445 and UniProtKB: Q02297.

[0004] The NRG1 isomorphic system is produced by alternative splicing and includes transmembrane, external membrane binding, shed, secretion, or intracellular forms (Falls' Exp Cell Res 284: 14–30, 2003; Hayes and Gullick's J. Mammary Gland Biol Neoplasia 13: 205-214, 2008). These are bound to ErbB-3 or ErbB-4, which can be understood as promoting the formation of heterodimers with ErbB-2 (HER2). Although the NRG1-encoded protein is generally considered a mitogen, it can also strongly promote apoptosis: in particular, the expression of NRG1 in cells can cause apoptosis in those cells (see Weinstein et al. oncogene 17: 2107–2113, 1998).

[0005] Given the various tumor types with NRG1 fusions, there is a need for faster and more robust diagnostic methods based on new fusion companions and new breakpoints between NRG1 and fusion companions, as well as methods for identifying previously unknown NRG fusions. [Summary of the Invention]

[0007] This disclosure generally provides fusions involving NRG1 and novel fusion partners, and peptide fusions encoded therefrom. This disclosure provides a fusion involving NRG1 and VAPB, NRG1 and PVALB, NRG1 and DAAM1, NRG1 and ASPH, NRG1 and ZFAT, or NRG1 and DSCAML1 as novel fusion partners, which generally refer to VAPB-NRG1, PVALB-NRG1, DAAM1-NRG1, ASPH-NRG1, ZFAT-NRG1, and DSCAML1-NRG1, respectively. More specifically, the states disclosed herein relate to: polynucleotides containing a VAPB nucleic acid sequence or a portion thereof fused with a portion thereof or a portion thereof of an NRG1 nucleic acid sequence; polynucleotides containing a PVALB nucleic acid sequence or a portion thereof fused with a portion thereof of an NRG1 nucleic acid sequence; polynucleotides containing a DAAM1 nucleic acid sequence or a portion thereof fused with a portion thereof of an NRG1 nucleic acid sequence; polynucleotides containing an ASPH nucleic acid sequence or a portion thereof fused with a portion thereof of an NRG1 nucleic acid sequence; polynucleotides containing a ZFAT nucleic acid sequence or a portion thereof fused with a portion thereof of an NRG1 nucleic acid sequence; and polynucleotides containing a DSCAML1 nucleic acid sequence or a portion thereof fused with a portion thereof of an NRG1 nucleic acid sequence.

[0008] Preferably, the VAPB nucleic acid sequence comprises or consists of any one of SEQ ID NO: 17-23, or comprises or consists of a pairwise variant of any one of SEQ ID NO: 17-23. Preferably, the NRG1 nucleic acid sequence comprises or consists of any one of SEQ ID NO: 125-138, or comprises or consists of a pairwise variant of any one of SEQ ID NO: 125-138.

[0009] Alternatively or otherwise, this disclosure provides a polynucleotide comprising a portion of exon 1 of VAPB or a variant of the opposite gene of exon 1, and which is fused with a portion of exon 2 of NRG1 or a variant of the opposite gene of exon 2. Preferably, exon 1 of VAPB comprises or consists of SEQ ID NO: 17, and its opposite gene variant is preferably a variant of SEQ ID NO: 17. Exon 2 of NRG1 comprises or consists of SEQ ID NO: 126, and its opposite gene variant is preferably a variant of SEQ ID NO: 126.

[0010] Preferably, the PVALB nucleic acid sequence comprises or consists of any one of SEQ ID NO: 439-444, or comprises or consists of a pairwise variant of any one of SEQ ID NO: 439-444. Preferably, the NRG1 nucleic acid sequence comprises or consists of any one of SEQ ID NO: 125-138, or comprises or consists of a pairwise variant of any one of SEQ ID NO: 125-138.

[0011] Alternatively or otherwise, this disclosure provides a polynucleotide comprising a portion of exon 4 of PVALB or a variant thereof, fused to a portion of exon 6 of NRG1 or a variant thereof. Preferably, exon 4 of PVALB comprises or is composed of SEQ ID NO: 422, and its variant thereof is preferably a variant of SEQ ID NO: 422. Exon 6 of NRG1 comprises or is composed of SEQ ID NO: 130, and its variant thereof is preferably a variant of SEQ ID NO: 130.

[0012] Preferably, the DAAM1 nucleic acid sequence comprises or consists of any one of SEQ ID NO: 606-631, or comprises or consists of a pairwise variant of any one of SEQ ID NO: 606-631. Preferably, the NRG1 nucleic acid sequence comprises or consists of any one of SEQ ID NO: 125-138, or comprises or consists of a pairwise variant of any one of SEQ ID NO: 125-138.

[0013] Alternatively or otherwise, this disclosure provides a polynucleotide comprising a portion of exon 1 of DAAM1 or a variant thereof, and which is fused with a portion of exon 1 of NRG1 or a variant thereof. Preferably, exon 1 of DAAM1 comprises or consists of SEQ ID NO: 606, and its variant thereof is preferably a variant of SEQ ID NO: 606. Exon 1 of NRG1 comprises or consists of SEQ ID NO: 125, and its variant thereof is preferably a variant of SEQ ID NO: 125.

[0014] Preferably, the ASPH nucleic acid sequence comprises or consists of any one of SEQ ID NO: 637-662, or comprises or consists of a pairwise variant of any one of SEQ ID NO: 637-662. Preferably, the NRG1 nucleic acid sequence comprises or consists of any one of SEQ ID NO: 125-138, or comprises or consists of a pairwise variant of any one of SEQ ID NO: 125-138.

[0015] Alternatively or otherwise, this disclosure provides a polynucleotide comprising a portion of exon 22 of ASPH or a variant thereof, and which is fused to a portion of exon 2 of NRG1 or a variant thereof. Preferably, exon 22 of ASPH comprises or is composed of SEQ ID NO: 658, and its variant thereof is preferably a variant of SEQ ID NO: 658. Exon 2 of NRG1 comprises or is composed of SEQ ID NO: 126, and its variant thereof is preferably a variant of SEQ ID NO: 126.

[0016] Preferably, the ZFAT nucleic acid sequence comprises or consists of any one of SEQ ID NO: 830-846, or comprises or consists of a pairwise variant of any one of SEQ ID NO: 830-846. Preferably, the NRG1 nucleic acid sequence comprises or consists of any one of SEQ ID NO: 125-138, or comprises or consists of a pairwise variant of any one of SEQ ID NO: 125-138.

[0017] Alternatively or otherwise, this disclosure provides a polynucleotide comprising a portion of exon 12 of ZFAT or a variant thereof, fused to a portion of exon 6 of NRG1 or a variant thereof. Preferably, exon 12 of ZFAT comprises or is composed of SEQ ID NO: 841, and its variant thereof is preferably a variant of SEQ ID NO: 841. Exon 6 of NRG1 comprises or is composed of SEQ ID NO: 130, and its variant thereof is preferably a variant of SEQ ID NO: 130.

[0018] Preferably, the DSCAML1 nucleic acid sequence comprises or consists of any one of SEQ ID NO: 870-903, or comprises or consists of a pairwise variant of any one of SEQ ID NO: 870-903. Preferably, the NRG1 nucleic acid sequence comprises or consists of any one of SEQ ID NO: 125-138, or comprises or consists of a pairwise variant of any one of SEQ ID NO: 125-138.

[0019] Alternatively or otherwise, this disclosure provides a polynucleotide comprising a portion of exon 3 of DSCAML1 or a portion of the dual gene variant of exon 3, fused with a portion of exon 2 of NRG1 or a portion of the dual gene variant of exon 2. Preferably, exon 3 of DSCAML1 comprises or consists of SEQ ID NO: 872, and its dual gene variant is preferably a variant of SEQ ID NO: 872. Exon 2 of NRG1 comprises or consists of SEQ ID NO: 126, and its dual gene variant is preferably a variant of SEQ ID NO: 126.

[0020] Additionally, this disclosure provides fusions involving NRG1 with previously undisclosed fusion junctions, and fusions of peptides encoded therein. In particular, this disclosure further provides fusions involving NRG1 and CADM1, generally referring to CADM1-NRG1. This disclosure also provides fusions involving NRG1 and CD44, generally referring to CD44-NRG1. This disclosure also provides fusions involving NRG1 and SLC3A2, generally referring to SLC3A2-NRG1. This disclosure also provides fusions involving NRG1 and VTCN1, generally referring to VTCN1-NRG1. This disclosure also provides fusions involving NRG1 and CDH1, generally referring to CDH1-NRG1. This disclosure also provides fusions involving NRG1 and CXADR, generally referring to CXADR-NRG1. This disclosure also provides fusions involving NRG1 and GTF2E2, generally referring to GTF2E2-NRG1. This disclosure also provides fusions involving NRG1 and CSMD1, generally referring to CSMD1-NRG1. This disclosure also provides fusions involving NRG1 and PTN, generally referring to PTN-NRG1. This disclosure also provides fusions involving NRG1 and ST14, generally referring to ST14-NRG1. This disclosure also provides fusions involving NRG1 and THBS1, generally referring to THBS1-NRG1. This disclosure also provides fusions involving NRG1 and AGRN, generally referring to AGRN-NRG1. This disclosure also provides fusions involving NRG1 and APP, generally referring to APP-NRG1. This disclosure also provides fusions involving NRG1 and WRN, generally referring to WRN-NRG1. This disclosure also provides fusions involving NRG1 and NRG1, generally referring to NRG1-NRG1. This disclosure also provides fusions involving NRG1 and NOTCH2, generally referring to NOTCH2-NRG1. This disclosure also provides a fusion of NRG1 and CD74, generally referring to CD74-NRG1. This disclosure also provides a fusion of NRG1 and SDC4, generally referring to SDC4-NRG1. This disclosure also provides a fusion of NRG1 and SLC4A4, generally referring to SLC4A4-NRG1.

[0021] 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 variant thereof, and fused to a portion of exon 6 of NRG1 or a variant thereof. Preferably, exon 7 of CADM1 comprises or is composed of SEQ ID NO: 39, and its variant thereof is preferably a variant of SEQ ID NO: 39. Exon 6 of NRG1 comprises or is composed of SEQ ID NO: 130, and its variant thereof is preferably a variant of SEQ ID NO: 130.

[0022] In particular, this disclosure provides a polynucleotide comprising a portion of exon 5 of CD44 or a variant thereof, and fused to a portion of exon 2 of NRG1 or a variant thereof. Preferably, exon 5 of CD44 comprises or is composed of SEQ ID NO: 65, and its variant thereof is preferably a variant of SEQ ID NO: 65. Exon 2 of NRG1 comprises or is composed of SEQ ID NO: 126, and its variant thereof is preferably a variant of SEQ ID NO: 126.

[0023] In particular, this disclosure provides a polynucleotide comprising a portion of exon 5 of CD44 or a variant of the opposite gene of exon 5, and which is fused with a portion of exon 6 of NRG1 or a variant of the opposite gene of exon 6. Preferably, exon 5 of CD44 comprises or consists of SEQ ID NO: 65, and its opposite gene variant is preferably a variant of SEQ ID NO: 65. Exon 6 of NRG1 comprises or consists of SEQ ID NO: 130, and its opposite gene variant is preferably a variant of SEQ ID NO: 130.

[0024] In particular, this disclosure provides a polynucleotide comprising a portion of exon 1 of transcript 6 of SLC3A2 or a portion of the dual gene variant of exon 1 of transcript 6, fused with a portion of the dual gene variant of exon 5 or exon 2 of NRG1. Preferably, the exon of SLC3A2 comprises or is composed of SEQ ID NO: 103, and its dual gene variant is preferably a variant of SEQ ID NO: 103. Exon 5 of NRG1 comprises or is composed of SEQ ID NO: 129, and its dual gene variant is preferably a variant of SEQ ID NO: 129.

[0025] In particular, this disclosure provides a polynucleotide comprising a portion of exon 2 of VTCN1 or a variant of its opposite gene, fused with a portion of exon 2 of NRG1 or a variant of its opposite gene. Preferably, exon 2 of VTCN1 comprises or consists of SEQ ID NO: 169, and its opposite gene variant is preferably a variant of SEQ ID NO: 169. Exon 2 of NRG1 comprises or consists of SEQ ID NO: 126, and its opposite gene variant is preferably a variant of SEQ ID NO: 126.

[0026] In particular, this disclosure provides a polynucleotide comprising a portion of exon 11 of CDH1 or a variant thereof, and fused with a portion of exon 2 of NRG1 or a variant thereof. Preferably, exon 11 of CDH1 comprises or is composed of SEQ ID NO: 198, and its variant thereof is preferably a variant of SEQ ID NO: 198. Exon 2 of NRG1 comprises or is composed of SEQ ID NO: 126, and its variant thereof is preferably a variant of SEQ ID NO: 126.

[0027] In particular, this disclosure provides a polynucleotide comprising a portion of exon 1 of CXADR or a variant of the exon 1 dual gene, fused with a portion of exon 2 of NRG1 or a variant of the exon 2 dual gene. Preferably, exon 1 of CXADR comprises or is composed of SEQ ID NO: 219, and its dual gene variant is preferably a variant of SEQ ID NO: 219. Exon 2 of NRG1 comprises or is composed of SEQ ID NO: 126, and its dual gene variant is preferably a variant of SEQ ID NO: 126.

[0028] In particular, this disclosure provides a polynucleotide comprising a portion of exon 2 of GTF2E2 or a variant thereof, and fused with a portion of exon 2 of NRG1 or a variant thereof. Preferably, exon 2 of GTF2E2 comprises or is composed of SEQ ID NO: 236, and its variant thereof is preferably a variant of SEQ ID NO: 236. Exon 2 of NRG1 comprises or is composed of SEQ ID NO: 126, and its variant thereof is preferably a variant of SEQ ID NO: 126.

[0029] In particular, this disclosure provides a polynucleotide comprising a portion of exon 23 of CSMD1 or a variant thereof, and fused to a portion of exon 6 of NRG1 or a variant thereof. Preferably, exon 23 of CSMD1 comprises or is composed of SEQ ID NO: 279, and its variant thereof is preferably a variant of SEQ ID NO: 279. Exon 6 of NRG1 comprises or is composed of SEQ ID NO: 130, and its variant thereof is preferably a variant of SEQ ID NO: 130.

[0030] In particular, this disclosure provides a polynucleotide comprising a portion of exon 4 of PTN or a variant thereof, and which is fused to a portion of exon 2 of NRG1 or a variant thereof. Preferably, exon 4 of PTN comprises or is composed of SEQ ID NO: 318, and its variant thereof is preferably a variant of SEQ ID NO: 318. Exon 2 of NRG1 comprises or is composed of SEQ ID NO: 126, and its variant thereof is preferably a variant of SEQ ID NO: 126.

[0031] In particular, this disclosure provides a polynucleotide comprising a portion of exon 11 of ST14 or a variant thereof, and fused to a portion of exon 6 of NRG1 or a variant thereof. Preferably, exon 11 of ST14 comprises or is composed of SEQ ID NO: 342, and its variant thereof is preferably a variant of SEQ ID NO: 342. Exon 6 of NRG1 comprises or is composed of SEQ ID NO: 130, and its variant thereof is preferably a variant of SEQ ID NO: 130.

[0032] In particular, this disclosure provides a polynucleotide comprising a portion of exon 9 of THBS1 or a variant thereof, and fused with a portion of exon 6 of NRG1 or a variant thereof. Preferably, exon 9 of THBS1 comprises or is composed of SEQ ID NO: 386, and its variant thereof is preferably a variant of SEQ ID NO: 386. Exon 6 of NRG1 comprises or is composed of SEQ ID NO: 130, and its variant thereof is preferably a variant of SEQ ID NO: 130.

[0033] In particular, this disclosure provides a polynucleotide comprising a portion of exon 12 of AGRN or a variant thereof, and fused to a portion of exon 6 of NRG1 or a variant thereof. Preferably, exon 12 of AGRN comprises or is composed of SEQ ID NO: 416, and its variant thereof is preferably a variant of SEQ ID NO: 416. Exon 6 of NRG1 comprises or is composed of SEQ ID NO: 130, and its variant thereof is preferably a variant of SEQ ID NO: 130.

[0034] In particular, this disclosure provides a polynucleotide comprising a portion of exon 4 of PVALB or a variant thereof, and fused with a portion of exon 6 of NRG1 or a variant thereof. Preferably, exon 4 of PVALB comprises or is composed of SEQ ID NO: 442, and its variant thereof is preferably a variant of SEQ ID NO: 442. Exon 6 of NRG1 comprises or is composed of SEQ ID NO: 130, and its variant thereof is preferably a variant of SEQ ID NO: 130.

[0035] In particular, this disclosure provides a polynucleotide comprising a portion of exon 2 of transcript 3 or a portion of the dual gene variant of exon 2 of transcript 3 of SLC3A2, fused to exon 6 of NRG1 or a portion of the dual gene variant of exon 6. Preferably, the exon of SLC3A2 comprises or is composed of SEQ ID NO: 457, and its dual gene variant is preferably a variant of SEQ ID NO: 457. Exon 6 of NRG1 comprises or is composed of SEQ ID NO: 130, and its dual gene variant is preferably a variant of SEQ ID NO: 130.

[0036] In particular, this disclosure provides a polynucleotide comprising a portion of exon 14 of APP or a variant thereof, and fused to a portion of exon 6 of NRG1 or a variant thereof. Preferably, exon 14 of APP comprises or is composed of SEQ ID NO: 501, and its variant thereof is preferably a variant of SEQ ID NO: 501. Exon 6 of NRG1 comprises or is composed of SEQ ID NO: 130, and its variant thereof is preferably a variant of SEQ ID NO: 130.

[0037] In particular, this disclosure provides a polynucleotide comprising a portion of exon 33 of WRN or a variant thereof, and which is fused to a portion of exon 6 of NRG1 or a variant thereof. Preferably, exon 33 of WRN comprises or is composed of SEQ ID NO: 562, and its variant thereof is preferably a variant of SEQ ID NO: 562. Exon 6 of NRG1 comprises or is composed of SEQ ID NO: 130, and its variant thereof is preferably a variant of SEQ ID NO: 130.

[0038] In particular, this disclosure provides a polynucleotide comprising a portion of exon 6 of NOTCH2 or a variant thereof, and fused with a portion of exon 6 of NRG1 or a variant thereof. Preferably, exon 6 of NOTCH2 comprises or is composed of SEQ ID NO: 700, and its variant thereof is preferably a variant of SEQ ID NO: 700. Exon 6 of NRG1 comprises or is composed of SEQ ID NO: 130, and its variant thereof is preferably a variant of SEQ ID NO: 130.

[0039] In particular, this disclosure provides a polynucleotide comprising a portion of exon 2 of CD74 or a variant of the exon 2 pair gene, fused with a portion of exon 2 of NRG1 or a variant of the exon 2 pair gene. Preferably, exon 2 of CD74 comprises or consists of SEQ ID NO: 720, and its variant is preferably a variant of SEQ ID NO: 720. Exon 2 of NRG1 comprises or consists of SEQ ID NO: 126, and its variant is preferably a variant of SEQ ID NO: 126.

[0040] In particular, this disclosure provides a polynucleotide comprising a portion of exon 2 of SDC4 or a variant of its opposite gene, fused with a portion of exon 2 of NRG1 or a variant of its opposite gene. Preferably, exon 2 of SDC4 comprises or consists of SEQ ID NO: 746, and its opposite gene variant is preferably a variant of SEQ ID NO: 746. Exon 2 of NRG1 comprises or consists of SEQ ID NO: 126, and its opposite gene variant is preferably a variant of SEQ ID NO: 126.

[0041] In particular, this disclosure provides a polynucleotide comprising a portion of exon 4 of SDC4 or a variant thereof, and which is fused to a portion of exon 2 of NRG1 or a variant thereof. Preferably, exon 4 of SDC4 comprises or is composed of SEQ ID NO: 748, and its variant thereof is preferably a variant of SEQ ID NO: 748. Exon 2 of NRG1 comprises or is composed of SEQ ID NO: 126, and its variant thereof is preferably a variant of SEQ ID NO: 126.

[0042] In particular, this disclosure provides a polynucleotide comprising a portion of exon 14 of SLC4A4 or a variant thereof, and fused with a portion of exon 6 of NRG1 or a variant thereof. Preferably, exon 14 of SLC4A4 comprises or is composed of SEQ ID NO: 780, and its variant thereof is preferably a variant of SEQ ID NO: 780. Exon 6 of NRG1 comprises or is composed of SEQ ID NO: 130, and its variant thereof is preferably a variant of SEQ ID NO: 130.

[0043] The NRG1 fusions described herein have all been observed in patient-derived samples, especially those from patients diagnosed with cancer.

[0044] The disclosed identification of such NRG1 fusions and gene rearrangements can provide new methods for determining the presence of NRG1 polynucleotide fusions or peptides in or from biological samples, methods for measuring the activity of NRG1 peptide fusions, methods for diagnosing cancers, tumors, or abnormal cells that express NRG1 peptide fusions, methods for treating cancers, tumors, or abnormal cells that express NRG1 peptide fusions, and / or methods for inhibiting disease processes characterized by the expression of NRG1 polynucleotide fusions or peptides. This disclosure therefore also provides such or more variations, which are described in detail below.

[0045] This disclosure also provides peptide fusions encoded by any of the following polynucleotide fusions: 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. When any of the peptide fusions disclosed herein exhibits the aberrant cellular expression mentioned herein, it preferably also contains the EGF-like domain of NRG1. When any of the polynucleotide fusions disclosed herein is contained in the abnormal cells mentioned herein, it preferably contains an NRG1 exon encoding an EGF-like domain, such as exons 6, 7, or 8 of NRG1, and more preferably exons 6 and 7 of the NRG1 polynucleotide sequence.

[0046] A vector comprising the polynucleotide fusion disclosed herein, and a host cell comprising the polynucleotide and / or the vector are also provided. A method for manufacturing the polypeptide disclosed herein is also provided, comprising maintaining the recombinant host cell under conditions suitable for the expression of the polynucleotide, thereby expressing the polynucleotide fusion and generating a polypeptide fusion, followed by isolating or purifying the polypeptide. A method for manufacturing a recombinant host cell is also provided, comprising introducing the vector into a host cell.

[0047] Also provided is a nucleic acid probe, primer, or primer pair for detecting the polynucleotide fusion of the present disclosure, and a detection assay comprising a nucleic acid probe, primer, or primer pair for detecting the presence of the polynucleotide fusion of the present disclosure. The length of such nucleic acid probes, primers, or primer pairs disclosed herein is preferably 10-40 nucleotides.

[0048] A first antibody or a first and second antibody pair is also provided for detecting a polypeptide encoded by the polynucleotide fusion of the present disclosure, and a detection assay method comprising the first antibody or the first and second antibody pair for detecting the presence of the polypeptide encoded by the polynucleotide fusion of the present disclosure. Preferably, the first antibody binds to a peptide fusion selected from the following: 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... The antibody pairs bind to VAPB and 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, respectively.

[0049] This disclosure includes methods for identifying or detecting NRG1 fusions in human individuals, and further covers methods and combinations thereof for diagnosis, treatment selection, and drug therapy to improve NRG1 fusion-related diseases, including solid tumors. In addition, this disclosure provides direct diagnostic means or assays for rapidly assessing whether an individual has or is susceptible to cancer, tumors, or abnormal cells. This information on NRG1 fusions can be advantageously used as biomarkers in diagnostic tools.

[0050] Therefore, a method is also provided for identifying any polynucleotide fusion as mentioned herein, or polypeptide encoded therefrom, in a sample, the method comprising examining a sample obtained from an individual to detect the presence of the fusion in the sample.

[0051] A method is also provided for detecting in a sample the presence of any polynucleotide fusion as mentioned herein, or a polypeptide encoded therefrom, the method comprising examining a sample obtained from an individual to detect the presence of the fusion in the sample.

[0052] A method is also provided for determining whether an abnormal cell (such as a cancer cell or a tumor cell) from an individual contains any of the polynucleotide fusions mentioned herein, or polypeptides encoded therefrom, the method comprising examining whether the fusion is present in a sample of a cell obtained from the individual or of the polynucleotide or polypeptide contents of the cell.

[0053] A method is also provided for identifying an individual carrying the polynucleotide fusion as described herein, or a polypeptide encoded therefrom, the method comprising examining a sample obtained from an individual to detect the presence of the fusion in the sample. Preferably, the examination is followed by a step of associating the fusion detected in the sample with an individual carrying the fusion.

[0054] The testing of the samples mentioned herein is preferably performed as a live in vitro analysis or such method, or as part of an ex vivo analysis or such method.

[0055] Preferably, the individual is a mammal or a human individual, and the polynucleotide or polypeptide is a mammalian or human polynucleotide or polypeptide.

[0056] Preferably, any polynucleotide fusion mentioned herein and / or the polypeptide encoded therefrom is isolated and / or purified or substantially isolated or purified.

[0057] This disclosure pertains to individuals who have cancer or are suspected of having cancer (especially solid cancers or tumors). In particular, these cancers are adenocarcinomas, especially mucinous adenocarcinomas, pancreatic cancers, especially pancreatic adenocarcinomas, or renal cell carcinomas, bile duct cancers, brain cancers, glioblastomas, bile duct cancers, gliomas, pancreatic duct adenocarcinomas, sarcomas, bladder cancers, colorectal cancers, rectal cancers, gallbladder cancers, head and neck cancers, prostate cancers, uterine cancers, breast cancers, ovarian cancers, liver cancers, endometrial cancers, lung cancers, especially non-small cell lung cancers, or invasive mucinous adenocarcinomas. These cancers can be primary or metastatic.

[0058] This disclosure also provides a method for treating an individual with ErbB-2 and / or ErbB-3 positive abnormal cells (such as cancer or tumors), said abnormal cells comprising the polynucleotide fusions mentioned herein, and / or such cells exhibiting polypeptide fusions encoded therein, said method comprising administering a therapeutic amount of an ErbB-2 and / or ErbB-3 target to the individual. Preferably, the polynucleotide or polypeptide fusions mentioned herein are detected prior to administration of said target.

[0059] This disclosure also provides a method for inhibiting the disease course of an individual suffering from ErbB-2 and ErbB-3 positive abnormal cells, said abnormal cells comprising the polynucleotide fusions mentioned herein and / or expressing polypeptide fusions encoded therein, said method comprising administering a therapeutic amount of an ErbB-2 and / or ErbB-3 target to the individual. Preferably, the polynucleotide or polypeptide fusions mentioned herein are detected prior to administration of said target.

[0060] This disclosure also provides an ErbB-2 and / or ErbB-3 target for use in the treatment of an individual with ErbB-2 and ErbB-3 positive cancer or tumor, said cancer or tumor comprising the polynucleotide fusions mentioned herein and / or exhibiting peptide fusions encoded therein, said treatment comprising administering a therapeutic amount of the ErbB-2 and / or ErbB-3 target to the individual. Preferably, the polynucleotide or peptide fusions mentioned herein are detected prior to administration of said target.

[0061] This disclosure also provides a method for diagnosing an individual with abnormal cells containing a polypeptide encoded by a polynucleotide fusion mentioned herein, the method comprising examining a sample obtained from the individual to detect the presence of the fusion in the sample.

[0062] This disclosure also provides a treatment method or use of ErbB-2 and / or ErbB-3 targets, wherein an individual is screened for the presence of the NGR1 fusion mentioned herein, and then ErbB-2 and / or ErbB-3 targets are administered.

[0063] This disclosure also includes in vivo models, such as xenograft or gene-transplanted animal models of transplanted abnormal cells that express or contain the polynucleotide fusions mentioned herein, and / or express the polypeptide fusions encoded therein, and treatment of such models using ERB2 and / or Erb3 targets or other targets. Preferably, the animal model is a non-human animal model.

Implementation Method

[0065] This disclosure provides fusions involving NRG1 and novel fusion partners, and polypeptide fusions encoded therefrom. Furthermore, this disclosure provides fusions involving NRG1 having previously undisclosed fusion junctions, and polypeptide fusions encoded therefrom.

[0066] Generally, this disclosure provides a fusion involving NRG1 and a fusion partner system 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 fusions referred to herein are 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 of the NRG1 fusions disclosed herein, whether polynucleotides or polypeptides translated from them, indicates the presence of abnormal cells (such as cancer or tumors). NRG1

[0067] The NRG1 gene encodes various NRG1 isoforms. The 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; and the SMDF isoform shares only the EGF-like domain with 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). This family has four members: ErbB-1 (erythroblastoma), ErbB-2, ErbB-3, and ErbB-4. The receptor (reviewed in Yarden and Pines, Nat Rev Cancer. 2012 Jul 12;12(8):553-63) is widely expressed on epithelial cells. Upregulation of the expression of the HER receptor or its ligands, such as heregulin (HRG) or epidermal growth factor (EGF), is a common event in human cancers (Wilson, Fridlyand et al., Nature. 2012 Jul 26; 487(7408): 505–509). Overexpression of ErbB-1 and ErbB-2 occurs particularly in epithelial tumors and is associated with tumor invasion, metastasis, chemotherapy resistance, 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 in the growth and differentiation of luminal epithelium. For example, loss / inhibition of ErbB-3 leads to selective basal expansion on luminal epithelium (Balko, Miller et al., 2012 PNAS January 3, 2012 109 (1) 221-226). The binding of the ligand to the extracellular domain of the tyrosine kinase receptor induces receptor dimerization, which is between the same (homodimerization) and different (heterodimerization) receptor subtypes.Dimerization can activate intracellular tyrosine kinase domains, leading to autophosphorylation of these domains and subsequent activation of numerous downstream pro-proliferative signaling pathways, including those mediated by mitogen-activated protein kinase (MAPK) and the survival-promoting Akt pathway (reviewed in Yarden and Pines, 2012). ErbB-3 can be activated by binding to its ligands. These ligands include, but are not limited to, neuroregulatory proteins (NRGs) and neuromodulatory factors (HRGs), as well as NRG1 fusions.

[0068] Various NRG1 fusion gene lines 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.

[0069] The term “NRG1” as used herein is not intended to be limited to any form such as protein, RNA, mRNA, cDNA or DNA sequence, but includes all such forms unless the context clearly indicates which form. The NRG1 gene and its isoforms are known by many different names, such as: Neuregulin 1; Pro-NRG1; HRGA; SMDF; HGL; GGF; NDF; NRG1 Intronic Transcript 2 (not encoding a protein); Heregulin, α (45kD, ERBB2 P185 activator); Acetylcholine Receptor-Inducing Activity; Pro-Neuregulin-1 (a membrane-bound isoform); Sensory and Motor Neuron Derivative Factor; Neu Differentiation Factor; Glial Growth Factor 2; NRG1-IT2; MSTP131; MST131; ARIA; GGF2; HRG1; and HRG. The external IDs of the NRG1 gene are HGNC: 7997; Entrez Gene: 3084; Ensembl: ENSG00000157168; OMIM: 142445 and UniProtKB: Q02297. For the avoidance of doubt, "NRG1 sequence" refers to any polynucleotide sequence, including coding sequences or any exons, but also any polypeptide sequence, or any part thereof, from a variant of the paired gene such as the NCBI reference sequence NM_001159999.3 or NM_001159999.3. Preferably, the full polynucleotide sequence of NRG1 disclosed herein is transcribed according to SEQ ID NO: 138, and the transcribed NRG1 polypeptide sequence is transcribed according to SEQ ID NO: 152.

[0070] Preferably, the polynucleotide fusion portion encoding the NRG1 protein sequence or NRG1 exon further includes or encodes an EGF-like domain of NRG1. The NRG1 gene in the fusion (e.g., the 3' end of the NRG1 gene) preferably includes the coding sequence for exon 6, 7, or 8. This domain is encoded by a portion located at the 3' end of the NRG1 gene (e.g., exons 6-8) and is essential for binding to ErbB-3. The NRG1 fusion gene preferably includes a nucleic acid sequence encoding the EGF-like domain of NRG1. The NRG1 fusions disclosed herein preferably retain a reading frame coding region of this EGF-like domain at the 3' end of the fusion molecule. EGF-like domains are typically sequences of about thirty to forty amino acid residues in length, and their prototypes are 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 exist in a largely conserved form in numerous other proteins, primarily animal proteins. A common characteristic of EGF-like domains is that they are found in the extracellular domains of membrane-bound proteins or in known secreted proteins (except for prostaglandin G / H synthase). EGF-like domains generally include six cysteine ​​residues and have been shown to involve disulfide bonds (in EGF). The main structure is a double-stranded β-lamellae followed by a short double-stranded lamellae looped to the C-terminus. The subdomains between conserved cysteine ​​residues vary in length. The exemplary EGF-like domain disclosed herein preferably consists of exons 6-8 of the NCBI reference sequence NM_001159999.3, more preferably exons 6 and 7, but this disclosure pertains to any functional EGF-like domain of NRG1. The EGF-like domain of NRG1 therefore preferably includes the exemplary sequence HLVKCAEKEKTFCVNGGECFMVKDLSNPSRYLCKCPNEFTGDRCQNYVMASF (SEQ ID: 163), or a paired gene variant that has at least 85% identity with it, or at least 90%, 92%, 94%, 95%, 96%, or even at least 98% identity with it.

[0071] Preferably, any NRG1 fusion polynucleotide disclosed herein comprises 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 for fusion with the 3' portion of the NRG1 nucleic acid sequence. The translated polypeptide fusion comprises the free C-terminus of the NRG1 fusion polypeptide and the free N-terminus of the fusion partner. To achieve this alignment at the molecular fusion level, any fusion partner of NRG1 is mentioned first, followed by NRG1 as its fusion partner. VAPB

[0072] VAPB, or vesicle-associated membrane protein B / C, is known by many different names, such as VAMP-associated protein B and C; VAMP (vesicle-associated membrane protein)-associated protein B and C; VAP-B; VAPB; ALS8; VAMP-associated 33 kDa protein; VAMP-associated protein B / C; VAMP-B / VAMP-C; VAP-B / VAP-C; VAMP-B and VAP-C. The external IDs of the VAPB gene are HGNC: 12649; Entrez Gene: 9217; Ensembl: ENSG00000124164; OMIM: 605704; and UniProtKB: O95292. The term "VAPB" as used herein is not intended to be limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context clearly indicates which form is being referred to. To avoid any confusion, "VAPB sequence" refers to any polynucleotide sequence derived from, for example, the NCBI reference sequence NM_004738.4 or any of its paired gene variants, including coding sequences or any exons, but also any polypeptide sequence or any part thereof. CADM1

[0073] CADM1 or cell adhesion molecule 1 is known by many different names, such as lung cancer 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; truncated CADM1 protein 1 and STSLC-1. The external IDs of CADM1 are HGNC: 5951; Entrez Gene: 23705; Ensembl: ENSG00000182985; OMIM: 605686; and UniProtKB: Q9BY67. The term "CADM1" as used herein is not limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context clearly indicates which form. For the avoidance of doubt, a CADM1 sequence refers to any polynucleotide sequence, including coding sequences or any exons, but also any polypeptide sequence or any part thereof, derived from NCBI reference sequence NM_001301045.1 or any of its paired gene variants, such as CD44.

[0074] CD44 is known by many different names, such as CD44 molecule (Indian blood group); hematopoietic cell E- and L-selective ligands; GP90 lymphocyte homing / adhesion receptor; chondroitin sulfate proteoglycan; extracellular matrix receptor III; chondroitin 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 of the CD44 gene are HGNC: 1681; Entrez Gene: 960; Ensembl: ENSG00000026508; OMIM: 107269; and UniProtKB: P16070. The term "CD44" as used herein is not limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context clearly indicates which form. For the avoidance of doubt, "with NRG1 sequence" refers to any polynucleotide sequence, including coding sequences or any exons, but also any polypeptide sequence or any part thereof, derived from a variant of the CD44 reference sequence NM_000610.4 or any of its paired genes. SLC3A2

[0075] SLC3A2 or solute carrier family 3 member 2 is known by many different names, such as lymphocyte activation antigen 4F2 large subunit; solute carrier family 3 (dibasic and neutral amino acid transport activator), member 2; antigen recognized by monoclonal antibodies 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; antigen defined by monoclonal antibody 4F2, heavy chain; antigen defined by monoclonal antibody 4F2; 4F2 heavy chain antigen; 4F2 heavy chain; 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. The term "SLC3A2" as used herein is not limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context clearly indicates which form. For the avoidance of doubt, a transcript sequence containing SLC3A2 refers to any polynucleotide sequence, including coding sequences or any exons, but also any polypeptide sequence or any portion thereof, derived from NCBI reference sequence NM_001013251.3 or any of its paired gene variants. The presence of the SLC3A2 transcript 3 sequence refers to any polynucleotide sequence derived from, for example, the NCBI reference sequence NM_001013251.3 or any of its paired gene variants, including coding sequences or any exons, but also any polypeptide sequences or any part thereof. VTCN1

[0076] VTCN1 is known by many different names, such as 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 of VTCN1 are HGNC: 28873; NCBI Entrez Gene: 79679; Ensembl: ENSG00000134258; OMIM®: 608162 and UniProtKB / Swiss-Prot: Q7Z7D3. The term "VTCN1" as used herein is not intended to be limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context clearly indicates which form. For the avoidance of doubt, a VTCN1 sequence refers to any nucleotide sequence containing a gene variant of NCBI reference sequence NM_024626.4 or any of its paired gene variants, including coding sequences or any exons, but also any polypeptide sequence or any portion thereof. CDH1

[0077] CDH1 or cadherin 1 is known by many different names, such as morula adhesion protein (Uvomorulin); cadherin 1, type 1, E-cadherin (epithelial); epithelial cadherin; E-cadherin; cadherin-1; CAM 120 / 80; CD324; CDHE; UVO; calcium-dependent adhesion protein, epithelial; epididymal secretory sperm-binding protein; cadherin 1, E-cadherin (epithelial); cell-CAM 120 / 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®: 192090 and UniProtKB / Swiss-Prot: P12830. The term "CDH1" as used herein is not limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context clearly indicates which form. For the avoidance of doubt, a CDH1 sequence refers to any nucleotide sequence from, such as the NCBI reference sequence NM_001317185.2 or any of its paired gene variants, including coding sequences or any exons, but also any polypeptide sequence, or any portion thereof. CXADR

[0078] CXADR, or Coxsackievirus and Adenovirus Receptor, is a type I membrane receptor for group B Coxsackievirus and subgroup C adenovirus. Several transcriptional variants encoding different isoforms of this gene have been identified. Diseases associated with CXADR include myocarditis and keratoconjunctivitis. Related pathways include adhesion and allogeneic transplant rejection. It is a component of the epithelial cell apical conjugation complex and acts as a homophilic cell adhesion molecule, crucial for the integrity of tight junctions. It is also involved in leukocyte migration across epithelial cells via adhesion interactions with the transmembrane protein JAML. The interaction between these two receptors also mediates the activation of γ-δ T cells, a subpopulation of T cells residing in epithelial cells, and is involved in tissue homeostasis and repair. Upon CXADR binding to epithelial cells, JAML mediates downstream cell signaling events in γ-δ T cells via PI3 and MAP kinases. This results in the proliferation and production of cytokines and growth factors through the corresponding stimulation of epithelial cell tissue repair by T cells. External IDs for CXADR include HGNC: 2559 NCBI; Entrez Gene: 1525; Ensembl: ENSG00000154639; OMIM®: 602621; UniProtKB / Swiss-Prot: P78310. The term "CXADR" as used herein is not intended to be limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context clearly indicates which form. For the avoidance of doubt, a CXADR sequence refers to any nucleotide sequence, including coding sequences or any exons, but also any polypeptide sequence or any portion thereof, derived from NCBI reference sequence NM_001207063.2 or any of its paired gene variants. GTF2E2

[0079] GTF2E2, or common transcription factor IIE (TFIIE), is part of the RNA polymerase II transcription initiation complex. It absorbs TFIIH and is absolutely essential for RNA polymerase II promoter clearance. TFIIE is a heterodimer (and sometimes a heterotetramer) containing both α and β subunits. The protein encoded by this gene represents the β subunit of TFIIE. Diseases associated with GTF2E2 include sulfur dysplasia 6 and non-photosensitive sulfur dysplasia. Related pathways include the apoptosis pathway in synovial fibroblasts and the CCR5 pathway in macrophages. External IDs for GTF2E2 include HGNC: 4651; NCBI Entrez Gene: 2961; Ensembl: ENSG00000197265; OMIM®: 189964; UniProtKB / Swiss-Prot: P29084. The term "GTF2E2" as used herein is not intended to be limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context clearly indicates which form. For the avoidance of doubt, a sequence containing GTF2E2 refers to any nucleotide sequence from, for example, the NCBI reference sequence NM_002095.6 or any of its paired gene variants, including coding sequences or any exons, but also any polypeptide sequence, or any portion thereof. CSMD1

[0080] CSMD1 (or CUB and Sushi multifunctional 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; UniProtKB / Swiss-Prot: Q96PZ7. The term "CSMD1" as used herein is not intended to be limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context clearly indicates which form. For the avoidance of doubt, a CSMD1 sequence refers to any nucleotide sequence containing a variant of NCBI reference sequence NM_033225.6 or any of its paired genes, including coding sequences or any exons, but also any polypeptide sequence or any portion thereof.

[0081] Pleiotrophin (PTN) is a secreted heparin-binding growth factor. This protein plays an important role in cell growth and survival, cell migration, angiogenesis, and tumorigenesis. PTN (Pleiotrophin) is a protein-coding gene. Diseases associated with PTN include Peyronie's disease and olfactory neuroblastoma of the nasal cavity. Related pathways include the GPCR pathway in synovial fibroblasts and the apoptosis pathway. External IDs for PTN include HGNC: 9630; NCBI Entrez Gene: 5764; Ensembl: ENSG00000105894; OMIM®: 162095; UniProtKB / Swiss-Prot: P21246. The term "PTN" as used herein is not limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context clearly indicates which form. To avoid any confusion, "PTN sequence" refers to any nucleotide sequence derived from, for example, the NCBI reference sequence NM_001321386.2 or any of its paired gene variants, including coding sequences or any exons, but also any polypeptide sequence or any part thereof. ST14

[0082] ST14, or ST14 transmembrane serine protease Matriptase, is an epithelial cell-derived membrane host protein serine protease. This protease forms a complex with the Kunitz-type serine protease inhibitor HAI-1 and has been found to be activated by sphingosine 1-phosphate. This protease has been shown to cleave and activate hepatocyte growth factor / split factor and urokinase plasminogen activator, suggesting its function as an epithelial cell membrane activator for other proteases and potential growth factors. Diseases associated with ST14 include various types of ichthyosis. Related pathways include developmental biology and adhesion. External IDs for ST14 include HGNC: 11344; NCBI Entrez Gene: 6768; Ensembl: ENSG00000149418; OMIM®: 606797; UniProtKB / Swiss-Prot: Q9Y5Y6. The term "ST14" as used herein is not intended to be limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context clearly indicates which form. For the avoidance of doubt, a sequence containing ST14 refers to any nucleotide sequence derived from, for example, the NCBI reference sequence NM_021978.4 or any of its paired gene variants, including coding sequences or any exons, but also any polypeptide sequence, or any portion thereof. THBS1

[0083] THBS1, or platelet-reactive protein 1, is a disulfide-linked homotrimeric protein subunit. This protein is an adhesive glycoprotein that mediates cell-cell interactions and cell-matrix interactions. It binds to fibrinogen, fibronectin, laminin, type V collagen, and integrin α-V / β-1. This protein has been shown to play important roles in platelet aggregation, angiogenesis, and tumorigenesis. Diseases associated with THBS1 include thrombotic thrombocytopenic purpura and Peters-Plus syndrome. Related pathways include the degradation of proteoglycans and extracellular matrix in cancer. Gene Ontology (GO) markers associated with this gene include calcium binding and heparin binding. External IDs for THBS1 include HGNC: 11785; NCBI Entrez Gene: 7057; Ensembl: ENSG00000137801; OMIM®: 188060; UniProtKB / Swiss-Prot: P07996. The term "THBS1" as used herein is not limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context clearly indicates which form. For the avoidance of doubt, a THBS1 sequence refers to any nucleotide sequence containing a variant of NCBI reference sequence NM_003246.4 or any of its paired genes, including coding sequences or any exons, but also any polypeptide sequence or any portion thereof. AGRN

[0084] AGRN, or agrin, is one of the important proteins in neuromuscular junction development. The encoded protein contains several laminin G, Kazal-type serine inhibitors, and epidermal growth factor domains. Other post-translational modifications include the addition of glycosaminoglycans and disulfide bonds. Mutations in this gene have been found in a gene family associated with congenital myasthenia gravis, affecting limb girdle muscles. Diseases associated with AGRN include myasthenia gravis, congenital, β-, and presynaptic congenital myasthenia gravis. Related pathways include agrin interactions at neuromuscular junctions, the blood-brain barrier, and immune cell translocation. External IDs for AGRN include HGNC: 329; NCBI Entrez Gene: 375790; Ensembl: ENSG00000188157; OMIM®: 103320; UniProtKB / Swiss-Prot: O00468. The term "AGRN" as used herein is not intended to be limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context clearly indicates which form. For the avoidance of doubt, a sequence containing AGRN refers to any nucleotide sequence, including coding sequences or any exons, but also any polypeptide sequence, or any portion thereof, derived from NCBI reference sequence NM_001305275.2 or any of its paired gene variants. PVALB

[0085] PVALB, or parvalbumin, is a high-affinity calcium-binding protein that is structurally and functionally similar to calmodulin and luciferin C. The encoded protein is thought to be involved in muscle relaxation. Diseases associated with PVALB include fish allergy and fetal alcohol syndrome. Genetic ontological markers associated with this gene include calcium binding and protein heterodimerization activity. External IDs for PVALB include HGNC: 9704; NCBI Entrez Gene: 5816; Ensembl: ENSG00000100362; OMIM®: 168890; UniProtKB / Swiss-Prot: P20472. The term "PVALB" as used herein is not limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context clearly indicates which form. To avoid any confusion, "PVALB sequence" refers to any nucleotide sequence derived from, for example, the NCBI reference sequence NM_002854.3 or any of its paired gene variants, including coding sequences or any exons, but also any polypeptide sequence or any part thereof. APP

[0086] APP is known to have many different names, such as amyloid β precursor protein, α-SAPP, AD1, Alzheimer's disease amyloid A4 protein homolog, amyloid β (A4) precursor protein, Alzheimer's disease amyloid protein, cerebral vascular amyloid peptide, amyloid β precursor protein, amyloid precursor protein, peptidase ligand protein (Nexin)-II, protease ligand protein-II, PN-II, PreA4, ABPP, APPI, CVAP, β-amyloid precursor protein, testicular tissue protein Li2, β-amyloid peptide (1-40), β-amyloid peptide (1-42), amyloid β-A4 protein, β-amyloid peptide, Alzheimer's disease, CTFγ, ABETA, AAA, PN2 and A4. The external IDs of the APP gene are HGNC: 620; Entrez Gene: 351; Ensembl: ENSG00000142192; OMIM®: 104760 and UniProtKB / Swiss-Prot: P05067. The term "APP" as used herein is not limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context clearly indicates which form. To avoid any confusion, "APP sequence" refers to any nucleotide sequence containing a gene variant of NCBI reference sequence NM_001136130.3 or any of its pairs, including coding sequences or any exons, but also any polypeptide sequence or any part thereof. WRN

[0087] WRN or Werner Syndrome ATP-dependent helicase is known by many different names, such as 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; EC 3.6.4.12; RECQL3; and RecQ3. The external IDs of the WRN gene are HGNC: 12791; NCBI Entrez Gene: 7486; Ensembl: ENSG00000165392; OMIM®: 604611; and UniProtKB / Swiss-Prot: Q14191. The term "WRN" as used herein is not intended to be limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context clearly indicates which form. For the avoidance of doubt, a WRN sequence refers to any nucleotide sequence containing a gene variant of NCBI reference sequence NM_000553.6 or any of its pairs, including coding sequences or any exons, but also any polypeptide sequence or any portion thereof. DAAM1

[0088] DAAM1, or morphogenesis disorder-associated activator 1, is known by many different names, such as KIAA0666; and morphogenesis disorder-associated activator 1. The external IDs of the DAAM1 gene are HGNC: 18142; NCBI Entrez Gene: 23002; Ensembl: ENSG00000100592; OMIM®: 606626; and UniProtKB / Swiss-Prot: Q9Y4D1. The term "DAAM1" as used herein is not intended to be limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context clearly indicates which form. For the avoidance of doubt, a DAAM1 sequence refers to any nucleotide sequence containing a variant of NCBI reference sequence NM_001270520.2 or any of its pairs, including coding sequences or any exons, but also any polypeptide sequence or any part thereof. ASPH

[0089] ASPH, or aspartic acid β-hydroxylase, is known by many different names, such as BAH, CASQ2BP1, JCTN, HAAH, aspartic acid / aspartic acid β-hydroxylase, peptide-aspartic acid β-dioxygenase, ASP β-hydroxylase, Junctate, Junctin, Humbug, Cardiac Junctin, EC 1.14.11.16, A β HJJ, FDLAB, and AAH. The external IDs of the ASPH gene are HGNC: 757; Entrez Gene: 444; Ensembl: ENSG00000198363; OMIM®: 600582 and UniProtKB / Swiss-Prot: Q12797. The term "ASPH" as used herein is not intended to be limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context clearly indicates which form. For the avoidance of doubt, an ASPH sequence refers to any nucleotide sequence containing a gene variant of NCBI reference sequence NM_001164750.2 or any of its paired gene variants, including coding sequences or any exons, but also any polypeptide sequence or any portion thereof. NOTCH2

[0090] NOTCH2 or Notch receptor 2 is known by many different names, such as Notch 2; neurogenic site gap homolog 2; HN2; Notch (Drosophila) homolog 2; Notch homolog 2 (Drosophila); Notch homolog 2; HJCYS; and AGS2. The external IDs of the NOTCH2 gene are HGNC: 7882; NCBI Entrez Gene: 4853; Ensembl: ENSG00000134250; OMIM®: 600275; and UniProtKB / Swiss-Prot: Q04721. The term "NOTCH2" as used herein is not intended to be limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context clearly indicates which form. To avoid any confusion, "NOTCH2 sequence" refers to any nucleotide sequence derived from, for example, the NCBI reference sequence NM_024408.4 or any of its paired gene variants, including coding sequences or any exons, but also any polypeptide sequence or any part thereof. CD74

[0091] CD74 is known by many different names, such as CD74 molecule; DHLAG; CD74 molecule, major histocompatibility complex, class II invariant chain; HLA class II histocompatibility antigen γ chain; class II MHC-associated invariant chain peptide; HLA-DR antigen-associated invariant chain; class II antigen γ chain; Ia-associated invariant chain; MHC HLA-DR γ chain; HLA-DR-γ; CLIP; Ia antigen-associated invariant chain; CD74 antigen; Ia-γ; HLA-ADG; P33; II; and Ii; the external ID of the CD74 gene is HGNC: 1697; NCBI Entrez Gene: 972; Ensembl: ENSG00000019582; OMIM®: 142790; and UniProtKB / Swiss-Prot: P04233. The term "CD74" as used herein is not intended to be limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context clearly indicates which form. For the avoidance of doubt, a CD74 sequence refers to any nucleotide sequence containing a gene variant of NCBI reference sequence NM_001025159.3 or any of its pairs, including coding sequences or any exons, but also any polypeptide sequence or any portion thereof. SDC4

[0092] SDC4, or Syndecan 4, is known by many different names, such as Amphiglycan; SYND4; Amphiglycan (Ryudocan); Ryudocan core protein; Syndecan-4; Ryudocan; and Ryudocan Amphiglycan. The external IDs of the SDC4 gene are HGNC: 10661; NCBI Entrez Gene: 6385; Ensembl: ENSG00000124145; OMIM®: 600017; and UniProtKB / Swiss-Prot: P31431. The term "SDC4" as used herein is not intended to be limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context clearly indicates which form. To avoid any confusion, the term "SDC4 sequence" refers to any nucleotide sequence derived from, for example, the NCBI reference sequence NM_002999.4 or any of its paired gene variants, including coding sequences or any exons, but also any polypeptide sequence or any portion thereof. SLC4A4

[0093] SLC4A4 or solute carrier family 4 member 4 is known to have many different names, such as NBC1; HNBC1; HhNMC; NBC2; PNBC; solute carrier family 4 (sodium bicarbonate cotransporter), member 4; potential-producing 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 5; sodium bicarbonate cotransporter; NBCe1-A; NBCE1; KNBC; and NBC. The external IDs of the SLC4A4 gene are HGNC: 11030; NCBI Entrez Gene: 8671; Ensembl: ENSG00000080493; OMIM®: 603345; and UniProtKB / Swiss-Prot: Q9Y6R1. The term "SLC4A4" as used herein is not limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context clearly indicates which form. For the avoidance of doubt, a sequence containing SLC4A4 refers to any nucleotide sequence from, for example, the NCBI reference sequence NM_001098484.3 or any of its paired gene variants, including coding sequences or any exons, but also any polypeptide sequence, or any portion thereof. ZFAT

[0094] ZFAT, or zinc finger containing an AT-hook domain, is known by many different names, such as zinc finger protein 406; KIAA1485; ZNF406; ZFAT1; zinc finger protein ZFAT; zinc finger gene in autoimmune thyroid disease; zinc finger gene in the AITD susceptibility region; and AITD3. The external IDs of the ZFAT gene are HGNC: 19899; NCBI Entrez Gene: 57623; Ensembl: ENSG00000066827; OMIM®: 610931; and UniProtKB / Swiss-Prot: Q9P243. The term "ZFAT" as used herein is not intended to be limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context clearly indicates which form. To avoid any confusion, "ZFAT sequence" refers to any nucleotide sequence derived from, for example, the NCBI reference sequence NM_020863.4 or any of its paired gene variants, including coding sequences or any exons, but also any polypeptide sequence or any part thereof. DSCAML1

[0095] DSCAML1, or DS-like cell adhesion molecule 1, is known by many different names, such as KIAA1132; Down syndrome-like cell adhesion molecule protein 1; Down syndrome-like cell adhesion molecule 2; DSCAM2; Down syndrome-like cell adhesion molecule 1; and DSCAM-like 1. The external IDs of the DSCAML1 gene are HGNC: 14656; NCBI Entrez Gene: 57453; Ensembl: ENSG00000177103; OMIM®: 611782; and UniProtKB / Swiss-Prot: Q8TD84. The term "DSCAML1" as used herein is not intended to be limited to any form such as protein, RNA, mRNA, cDNA, or DNA sequence, but includes all such forms unless the context clearly indicates which form. To avoid any confusion, "DSCAML1 sequence" refers to any nucleotide sequence derived from, for example, the NCBI reference sequence NM_020693.4 or any of its paired gene variants, including coding sequences or any exons, but also any polypeptide sequence or any part thereof. NRG1 polynucleotide fusions

[0096] According to this disclosure, previously unknown gene rearrangements that result in the expression of NRG1 fusion products fused with a fusion partner are now provided. 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. In particular, such fusions have been present or identified in human patients diagnosed with cancer, and will be discussed in more detail in the next section.

[0097] In some embodiments, the NRG1 fusion may include an additional downstream fusion partner at the 3' position of the sequence encoding the EGF-like domain. VAPB-NRG1 polynucleotide fusion

[0098] According to this disclosure, a polynucleotide comprising a fusion of a VAPB nucleic acid sequence (or a portion thereof) and an NRG1 nucleic acid sequence (or a portion thereof) is also provided. The fusion also includes variants of the VAPB and NRG1 nucleic acid sequences.

[0099] Preferably, the VAPB nucleic acid sequence (or a portion thereof) comprises, or is composed of, any of the pairs of SEQ ID NO: 17-23 or a variant thereof, of any of SEQ ID NO: 17-23, and the NRG1 nucleic acid sequence (or a portion thereof) comprises, or is composed of, any of the pairs of SEQ ID NO: 125-138 or a variant thereof. More preferably, the VAPB nucleic acid sequence comprises, or is composed of, a portion of a variant thereof, of SEQ ID NO: 23 or a variant thereof, and the NRG1 nucleic acid sequence comprises, or is composed of, a portion thereof, of a variant thereof, of SEQ ID NO: 138 or a variant thereof. SEQ ID NO: 17-22 correspond to individual exons 1-6 of the VAPB according to NM_004738.4. SEQ ID NO: 23 corresponds to exons 1-5 of VAPB according to NM_004738.4. SEQ ID NO: 125-137 correspond to individual exons 1-13 of NRG1 according to NM_001159999. SEQ ID NO: 138 corresponds to exons 1-13 of NRG1 according to NM_001159999.

[0100] In a preferred embodiment, the VAPB nucleic acid sequence portion comprises 2 to about 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from any of SEQ ID NO: 17-23 (or the dual gene variant of any of SEQ ID NO: 17-23), while the NRG1 nucleic acid sequence portion comprises 2 to about 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from any of SEQ ID NO: 125-138 (or the dual gene variant of any of SEQ ID NO: 125-138).

[0101] Preferably, the VAPB nucleic acid sequence or a portion thereof is located at the 5' position of the NRG1 nucleic acid sequence or a portion thereof.

[0102] Preferably, the polynucleotide comprising the fusion of the VAPB nucleic acid sequence (or a portion thereof) and the NRG1 nucleic acid sequence (or a portion thereof) contains or encodes the EGF-like domain of NRG1. Abnormal cell lines containing the VAPB-NRG1 polynucleotide fusion or expressing the polypeptide fusion contain or encode the EGF-like domain of NRG1. For detection, diagnosis, or identification purposes, it is sufficient to demonstrate that the fusion junction between VAPB and NRG1 is within a reading frame and occurs at a location that would allow the resulting fusion product, nucleic acid, or protein to contain the EGF-like domain of NRG1. The EGF-like domain is preferably the EGF-like domain of SEQ ID NO: 163 or its counterpart variant and has at least 85% identity with SEQ ID NO: 163, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0103] Preferably, the VAPB nucleic acid sequence pair gene variant has at least 85% identity with any of SEQ ID NO: 17-23, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity; and the NRG1 nucleic acid sequence pair gene variant has at least 85% identity with any of SEQ ID NO: 125-138, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity.

[0104] In a preferred embodiment, the polynucleotide comprising the fusion of VAPB nucleic acid and NRG1 nucleic acid comprises up to 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids from SEQ ID NO: 3, and preferably includes 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, and preferably includes at least the nucleic acids at positions 53 and 54.

[0105] In a preferred embodiment, a polynucleotide according to SEQ ID NO: 3 is provided, or a polynucleotide comprising about 20, about 30, about 40 or all of the consecutive nucleic acids from SEQ ID NO: 3, preferably including 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 of the nucleic acids from SEQ ID NO: 3, and preferably includes at least the nucleic acids at positions 43 and 44.

[0106] Preferably, the polynucleotide portion of the NRG1 nucleic acid sequence (or its dual gene variant) encodes the EGF-like domain of NRG1, more preferably the EGF-like domain according to SEQ ID NO: 163.

[0107] In an alternative state, a polynucleotide comprising a portion of exon 1 of VAPB or a variant thereof and a portion of exon 2 of NRG1 or a variant thereof is provided. Preferably, exon 1 of VAPB is exon SEQ ID NO: 17. Preferably, exon 2 of NRG1 is exon SEQ ID NO: 126. The portion of exon 1 of VAPB preferably comprises or is composed of SEQ ID NO: 1 or a variant thereof. The portion of exon 2 of NRG1 preferably comprises or is composed of SEQ ID NO: 2 or a variant thereof. When present in abnormal cells of a patient or individual, the polynucleotide fusion preferably further comprises any sequence at the 3' of exon 2 of NRG1, but the presence of at least SEQ ID NO: 17 and 126 may be sufficient for detection of the fusion junction using a polynucleotide-based assay. Any sequence from exon 2 to 3' of NRG1 contains one or all of, or is composed of, any of the pairs of gene variants of SEQ ID NO: 127-137 (or any of the pairs of gene variants of SEQ ID NO: 127-137).

[0108] Preferably, the VAPB exon 1 dual gene variant has at least 85% identity with SEQ ID NO: 17, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity, and the NRG1 exon 2 dual gene variant has at least 85% identity with SEQ ID NO: 126, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity.

[0109] In a preferred embodiment, the portion of exon 1 of VAPB comprises or consists of SEQ ID NO: 1, and its paired gene variant has at least 85% identity with SEQ ID NO: 1, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. The portion of exon 2 of NRG1 in this fusion comprises or consists of SEQ ID NO: 2, and its paired gene variant has at least 85% identity with SEQ ID NO: 2, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. Such short polynucleotide sequences are particularly advantageous for detecting the presence of large polynucleotide fusions between VAPB and NRG1 and for determining whether such fusions are oncogenic fusions containing an EGF-like domain of NRG1 that fits the reading frame. More preferably, the portion of exon 1 of VAPB comprises or consists of up to 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids from SEQ ID NO: 1, and includes at least the nucleic acid at position 43. 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: 1, and includes at least the nucleic acid at position 43. More preferably, the portion of exon 1 of VAPB comprises or is based on SEQ ID NO: 1 or its dual gene variant.

[0110] Alternatively, a portion of VAPB exon 1 comprises or is composed of SEQ ID NO: 17 (or a variant of SEQ ID NO: 17), including at least the nucleic acid at position 399. Preferably, a portion of VAPB exon 1 comprises or is composed of 2 to about 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids derived from SEQ ID NO: 17 or its variants, including at least the nucleic acid at position 399. 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, or 40, or all of the nucleic acids of SEQ ID NO: 17, and shall include at least the nucleic acid at position 399. In this alternative example, a portion of exon 1 of VAPB preferably comprises or is based on SEQ ID NO: 17 or its dual gene variant. Preferably, the NRG1 exon 2 portion of the fusion with VAPB comprises or consists of 2 to about 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from SEQ ID NO: 126 or its dual gene variant, and includes 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 or all of the nucleic acids from SEQ ID NO: 126, and includes at least the nucleic acid at position 1.

[0111] In an alternative preferred embodiment, the polynucleotide comprising a portion of VAPB exon 1 fused to a portion of NRG1 exon 2 comprises up to 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids from SEQ ID NO: 3, 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, or 40 or all of the nucleic acids from SEQ ID NO: 3, and at least includes the nucleic acids at positions 43 and 44. SEQ ID NO: 3 includes a junction between VAPB and NRG1, particularly between a nucleic acid originating from position 43 of VAPB and a nucleic acid originating from position 44 of NRG1. Preferably, the polynucleotide comprising a portion of exon 1 of VAPB and a portion of exon 2 of NRG1 has the polynucleotide sequence of SEQ ID NO: 3 or a variant thereof.

[0112] Preferably, any VAPB-NRG1 polynucleotide fusion provided herein is a fusion of a VAPB and NRG1 frame of reference. More preferably, the fusion is a fusion of a frame of reference containing exon 1 or a portion of exon 1 of VAPB and exon 2 or a portion of exon 2 of NRG1. The fusion of the frame of reference is preferably a fusion of SEQ ID NO: 3 or its opposite gene variant.

[0113] Preferably, a portion of VAPB exon 1 (or its paired gene variant) is located at the 5' of NRG1 exon 2 (or its paired gene variant). This nucleotide-level alignment results in the fusion polypeptide product containing the N-terminus of VAPB and the C-terminus of NRG1. Furthermore, the VAPB-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 VAPB, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, wherein the NRG1 portion also provides its EGF-like domain. The VAPB-NRG1 fusion protein thus retains the EGF-like domain of NRG1 and its ability to drive the proliferation and survival of a small group of human cancers, including lung or adenocarcinoma, particularly lung adenocarcinoma or non-small cell lung cancer. CADM1-NRG1 polynucleotide fusion

[0114] A polynucleotide fusion comprising a portion of exon 7 of CADM1 and a portion of exon 6 of NRG1 is also provided. Exon 7 of CADM1 is preferably an exon of the opposite gene variant of SEQ ID NO: 39 or SEQ ID NO: 39, and exon 6 of NRG1 is preferably an exon of the opposite gene variant of SEQ ID NO: 130 or SEQ ID NO: 130.

[0115] Preferably, the dual gene variant of exon 7 of CADM1 has at least 85% identity with SEQ ID NO: 39, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity, while the dual gene variant of exon 6 of NRG1 has at least 85% identity with SEQ ID NO: 130, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity.

[0116] Preferably, the exon 7 portion of CADM1 comprises or conforms to SEQ ID NO: 5, and its paired gene variant has at least 85% identity with SEQ ID NO: 5, more preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. The exon 6 portion of NRG1 in the fusion with CADM1 preferably comprises or conforms to the sequence of SEQ ID NO: 6, and its paired gene variant has at least 85% identity with SEQ ID NO: 6, more preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. Such short polynucleotide sequences are particularly advantageous for detecting the presence of large polynucleotide fusions between CADM1 and NRG1 and for determining whether such fusions are oncogenic fusions containing an EGF-like domain of NRG1 within a reading frame. More preferably, the exon 7 portion of CADM1 comprises or consists of 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 includes at least the nucleic acid at position 43. 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 includes at least the nucleic acid at position 53. More preferably, the exon 7 portion of CADM1 comprises or is based on SEQ ID NO: 5 or its dual gene variant.

[0117] Alternatively, the portion of exon 7 of CADM1 comprises or is composed of SEQ ID NO: 39 (or a variant of SEQ ID NO: 39), including at least the nucleic acid at position 173. Preferably, the portion of exon 7 of CADM1 comprises or is composed of 2 to about 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids derived from SEQ ID NO: 39 or its variants, including at least the nucleic acid at position 173. 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, or 40, or all of the nucleic acids of SEQ ID NO: 39, and shall include at least the nucleic acid at position 173. In this alternative example, a portion of exon 7 of CADM1 preferably comprises or is based on SEQ ID NO: 39 or its dual gene variant. Preferably, the NRG1 exon 6 portion of the fusion with CADM1 comprises or consists of 2 to about 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from SEQ ID NO: 130 or its dual gene variant, and includes 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 or all of the nucleic acids from SEQ ID NO: 130, and includes at least the nucleic acid at position 1.

[0118] In an alternative preferred embodiment, the polynucleotide comprising a portion of exon 7 of CADM1 and a portion of exon 6 of NRG1 comprises about 10, about 20, about 30, or up to about 40 or even all of the 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 from SEQ ID NO: 7, and at least includes the nucleic acids at positions 53 and 54. SEQ ID NO: 7 includes a junction between CADM1 and NRG1, particularly a junction located between a nucleic acid originating from position 53 of CADM1 and a nucleic acid originating from position 54 of NRG1. Preferably, the polynucleotide comprising a portion of exon 7 of CADM1 and a portion of exon 6 of NRG1 has the polynucleotide sequence of SEQ ID NO: 7 or a variant thereof.

[0119] In a preferred embodiment, a polynucleotide according to SEQ ID NO: 7 is provided, or a polynucleotide comprising about 20, about 30, about 40 or all of the consecutive nucleic acids from SEQ ID NO: 7, preferably including 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 of the nucleic acids from SEQ ID NO: 7, and preferably includes at least the nucleic acids at positions 53 and 54.

[0120] Preferably, any CADM1-NRG1 polynucleotide fusion provided herein is a fusion of a reading frame matching CADM1 and NRG1. More preferably, the fusion is a fusion of a reading frame matching CADM1 exon 7 or a portion of exon 7 and NRG1 exon 6 or a portion of exon 6. The fusion of the reading frame matching is preferably a fusion of SEQ ID NO: 7 or its dual gene variant, and the dual gene variant has at least 85% identity with SEQ ID NO: 7, preferably at least 90%, 92%, 94%, 96% or even 98% identity.

[0121] Preferably, the polynucleotide comprising a portion of CADM1 exon 7 (or a variant thereof) fused to a portion of NRG1 exon 6 (or a variant thereof) is a portion of a longer polynucleotide that further comprises or encodes an EGF-like domain of NRG1. Abnormal cell lines comprising polynucleotide fusions involving CADM1 or expressing the polypeptide fusion comprise or encode an EGF-like domain of NRG1. For rapid detection, diagnosis, or identification purposes, it is sufficient to demonstrate that the fusion junction between CADM1 and NRG1 is within a reading frame and occurs at a location where the resulting fusion product, nucleic acid, or protein comprises an EGF-like domain of NRG1. The EGF-like domain is preferably the EGF-like domain of SEQ ID NO: 163 or a variant thereof and has at least 85% identity with SEQ ID NO: 163, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0122] Preferably, a portion of exon 7 of CADM1 (or a variant thereof) is located at the 5' position of exon 6 of NRG1 (or a variant thereof). This alignment at the nucleic acid level results in the 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, wherein the NRG1 portion also provides its EGF-like domain. The CADM1-NRG1 fusion protein thus retains the EGF-like domain of NRG1 and its ability to drive the proliferation and survival of a small group of human cancers, including lung cancer or adenocarcinoma, especially lung adenocarcinoma.

[0123] When present in abnormal cells of a patient or individual, the CADM1-NRG1 polynucleotide fusion preferably further comprises any sequence at 5' of exon 7 of CADM1 and any sequence at 3' of exon 6 of NRG1, but the presence of at least SEQ ID NO: 39 and 130 may be sufficient for detection of the fusion junction using a polynucleotide-based assay. Any sequence from 5' of exon 7 of CADM1 comprises or consists of one or all of SEQ ID NO: 33-38 (or any pair variant of SEQ ID NO: 33-38), and any sequence from 3' of exon 6 of NRG1 comprises or consists of any or all of SEQ ID NO: 131-137 (or any pair variant of SEQ ID NO: 131-137). CD44-NRG1 polynucleotide fusion

[0124] A polynucleotide fusion comprising a portion of exon 5 of CD44 and a portion of exon 2 of NRG1 is also provided. Exon 5 of CD44 is preferably an exon of the opposite gene variant of SEQ ID NO: 65 or SEQ ID NO: 65, and exon 2 of NRG1 is preferably an exon of the opposite gene variant of SEQ ID NO: 126 or SEQ ID NO: 126.

[0125] Preferably, the CD44 exon 5 dual gene variant has at least 85% identity with SEQ ID NO: 65, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity, and the NRG1 exon 2 dual gene variant has at least 85% identity with SEQ ID NO: 126, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity.

[0126] Preferably, the portion of exon 5 of CD44 comprises or is based on SEQ ID NO: 9, and its dual gene variant has at least 85% identity with SEQ ID NO: 9, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. The portion of exon 2 of NRG1 in the fusion with CD44 preferably comprises or is based on the sequence of SEQ ID NO: 10, and its dual gene variant has at least 85% identity with SEQ ID NO: 10, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, the portion of exon 5 of CD44 comprises or is composed of up to 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids from SEQ ID NO: 9, and includes at least the nucleic acid at position 52. 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, or 40, or all of the nucleic acids of SEQ ID NO: 9, and at least include the nucleic acid at position 52. More preferably, the portion of exon 5 of CD44 contains or is based on SEQ ID NO: 9 or a variant thereof. Such short polynucleotide sequences are particularly useful for detecting the presence of large polynucleotide fusions between CD44 and NRG1 and for determining whether such fusions are oncogenic fusions containing an EGF-like domain of NRG1 within a reading frame.

[0127] Alternatively, the portion of CD44 exon 5 comprises or is composed of SEQ ID NO: 65 (or a variant of SEQ ID NO: 65), including at least the nucleic acid at position 231. Preferably, the portion of CD44 exon 5 comprises or is composed of 2 to about 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids derived from SEQ ID NO: 65 or its variant, including at least the nucleic acid at position 231. 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, or 40, or all of the nucleic acids of SEQ ID NO: 65, and shall include at least the nucleic acid at position 231. In this alternative example, the portion of CD44 exon 5 preferably comprises or is based on SEQ ID NO: 231 or its dual gene variant. Preferably, the NRG1 exon 2 portion of the fusion with CD44 comprises or consists of 2 to about 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from SEQ ID NO: 126 or its dual gene variant, and includes 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 or all of the nucleic acids from SEQ ID NO: 126, and includes at least the nucleic acid at position 1.

[0128] In an alternative preferred embodiment, the polynucleotide comprising a portion of CD44 exon 5 fused to a portion of NRG1 exon 2 comprises up to 10, about 20, about 30, or up to about 40 or even all of the 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 from SEQ ID NO: 11, and at least includes the nucleic acids at positions 52 and 53. SEQ ID NO: 11 includes a junction between CD44 and NRG1, particularly a junction between a nucleic acid originating from position 52 of CD44 and a nucleic acid originating from position 53 of NRG1. Preferably, the polynucleotide comprising a portion of exon 5 of CD44 and a portion of exon 2 of NRG1 has the polynucleotide sequence of SEQ ID NO: 15 or a variant thereof.

[0129] In a preferred embodiment, a polynucleotide according to SEQ ID NO: 11 is provided, or a polynucleotide comprising about 20, about 30, about 40 or all of the consecutive nucleic acids from SEQ ID NO: 11, preferably including 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 of the nucleic acids from SEQ ID NO: 11, and preferably includes at least the nucleic acids at positions 52 and 53.

[0130] Preferably, any CD44-NRG1 polynucleotide fusion provided herein is a fusion of a reading frame matching CD44 and NRG1. More preferably, the fusion is a fusion containing a reading frame matching CD44 exon 5 (or a portion of exon 5) and NRG1 exon 2 (or a portion of NRG1 exon 2). The fusion of the reading frame is preferably a fusion of SEQ ID NO: 11 or its dual gene variant, and the dual gene variant has at least 85% identity with SEQ ID NO: 11, preferably at least 90%, 92%, 94%, 96%, or even 98% identity.

[0131] Preferably, the polynucleotide comprising a portion of CD44 exon 5 (or a variant thereof) fused to a portion of NRG1 exon 2 (or a variant thereof) is a portion of a longer polynucleotide that further comprises or encodes an EGF-like domain of NRG1. Abnormal cell lines comprising polynucleotide fusions involving CD44 or expressing the polypeptide fusion comprise or encode an EGF-like domain of NRG1. For rapid detection, diagnosis, or identification purposes, it is sufficient to demonstrate that the fusion junction between CD44 and NRG1 is within a reading frame and occurs at a location where the resulting fusion product, nucleic acid, or protein comprises an EGF-like domain of NRG1. The EGF-like domain is preferably the EGF-like domain according to SEQ ID NO: 163 or a variant thereof and has at least 85% identity with SEQ ID NO: 163, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0132] Preferably, a portion of CD44 exon 5 (or its paired gene variant) is located at the 5' position of NRG1 exon 2 (or its paired gene variant). This nucleotide-level alignment results in the 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, wherein the NRG1 portion also provides its EGF-like domain. The CD44-NRG1 fusion protein thus retains the EGF-like domain of NRG1 and the ability to drive the proliferation and survival of a small group of human cancers, including pancreatic cancer or pancreatic adenocarcinoma, especially pancreatic ductal adenocarcinoma (or PDAC).

[0133] When present in abnormal cells of a patient or individual, the CD44-NRG1 polynucleotide fusion preferably further comprises any sequence at 5' of CD44 exon 5 and any sequence at 3' of NRG1 exon 2, but the presence of at least SEQ ID NO: 65 and 126 may be sufficient for detection of the fusion junction using a polynucleotide-based assay. Any sequence from 5' of CD44 exon 5 comprises or consists of one or all of SEQ ID NO: 61-64 (or any pair variant of SEQ ID NO: 61-64), and any sequence from 3' of NRG1 exon 6 comprises or consists of one or all of SEQ ID NO: 127-137 (or any pair variant of SEQ ID NO: 127-137).

[0134] Furthermore, a polynucleotide fusion comprising a portion of exon 5 of CD44 and a portion of exon 6 of NRG1 is provided. The CD44 exon 5 is preferably an exon of a variant of the paired gene of SEQ ID NO: 65 or SEQ ID NO: 65, and the NRG1 exon 6 is preferably an exon of a variant of the paired gene of SEQ ID NO: 130 or SEQ ID NO: 130.

[0135] Preferably, the variant of the CD44 exon 5 has at least 85% identity with SEQ ID NO: 65, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity, while the variant of the NRG1 exon 6 has at least 85% identity with SEQ ID NO: 130, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity.

[0136] Preferably, the portion of exon 5 of CD44 comprises or is based on SEQ ID NO: 759, and its dual gene variant has at least 85% identity with SEQ ID NO: 9, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. The portion of exon 6 of NRG1 in the fusion with CD44 preferably comprises or is based on the sequence of SEQ ID NO: 760, and its dual gene variant has at least 85% identity with SEQ ID NO: 760, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, the portion of exon 5 of CD44 comprises or is composed 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: 759, and includes 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, or 40, or all of the nucleic acids of SEQ ID NO: 759, and at least includes the nucleic acid at position 75. More preferably, the portion of exon 5 of CD44 comprises or is based on SEQ ID NO: 759 or a variant thereof. Such short polynucleotide sequences are particularly advantageous for detecting the presence of large polynucleotide fusions between CD44 and NRG1 and for determining whether such fusions are oncogenic fusions containing an EGF-like domain of NRG1 within a reading frame.

[0137] Alternatively, the portion of CD44 exon 5 comprises or is composed of SEQ ID NO: 65 (or a variant of SEQ ID NO: 65), including at least the nucleic acid at position 231. Preferably, the portion of CD44 exon 5 comprises or is composed of 2 to about 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids derived from SEQ ID NO: 65 or its variants, including at least the nucleic acid at position 231. 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, or 40, or all of the nucleic acids of SEQ ID NO: 65, and shall include at least the nucleic acid at position 231. In this alternative example, the portion of CD44 exon 5 preferably comprises or is based on SEQ ID NO: 65 or its dual gene variant. Preferably, the NRG1 exon 6 portion of the fusion with CD44 comprises 2 to about 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from SEQ ID NO: 130 or its dual gene variant, or is composed of such nucleic acids, and includes 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 or all of the nucleic acids from SEQ ID NO: 130, and includes at least the nucleic acid at position 1.

[0138] Preferably, any CD44-NRG1 polynucleotide fusion provided herein is a fusion of a reading frame matching CD44 and NRG1. More preferably, the fusion is a fusion of a reading frame matching CD44 exon 5 or a portion of exon 5 and NRG1 exon 6 or a portion of exon 6. The fusion of the reading frame is preferably a fusion of SEQ ID NO: 761 or its dual gene variant, and the dual gene variant has at least 85% identity with SEQ ID NO: 761, preferably at least 90%, 92%, 94%, 96% or even 98% identity.

[0139] In an alternative preferred embodiment, the polynucleotide comprising a portion of CD44 exon 5 fused to a portion of NRG1 exon 6 comprises up to 10, about 20, about 30, or up to about 40 or even all of the 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 from SEQ ID NO: 761, and at least includes the nucleic acids at positions 75 and 76. SEQ ID NO: 761 includes a junction between CD44 and NRG1, particularly a junction located between a nucleic acid originating from position 75 of CD44 and a nucleic acid originating from position 76 of NRG1. Preferably, the polynucleotide comprising a portion of exon 5 of CD44 and a portion of exon 6 of NRG1 has the polynucleotide sequence of SEQ ID NO: 761 or a variant thereof.

[0140] In a preferred embodiment, a polynucleotide according to SEQ ID NO: 761 is provided, or a polynucleotide comprising about 20, about 30, about 40 or all of the consecutive nucleic acids from SEQ ID NO: 761, preferably including 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 of the nucleic acids from SEQ ID NO: 761, and preferably includes at least the nucleic acids at positions 75 and 76.

[0141] Preferably, the polynucleotide comprising a portion of CD44 exon 5 (or a variant thereof) fused to a portion of NRG1 exon 6 (or a variant thereof) is a portion of a longer polynucleotide that further comprises or encodes an EGF-like domain of NRG1. Abnormal cell lines comprising polynucleotide fusions involving said CD44 or expressing the polypeptide fusion comprise or encode an EGF-like domain of NRG1. For rapid detection, diagnosis, or identification purposes, it is sufficient to demonstrate that the fusion junction between CD44 and NRG1 is frame-compliant and occurs at a location where the resulting fusion product, nucleic acid, or protein comprises an EGF-like domain of NRG1. The EGF-like domain is preferably the EGF-like domain according to SEQ ID NO: 163 or a variant thereof and has at least 85% identity with SEQ ID NO: 163, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0142] Preferably, a portion of CD44 exon 5 (or its paired gene variant) is located at the 5' position of NRG1 exon 6 (or its paired gene variant). This nucleic acid level alignment results in the 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, wherein the NRG1 portion also provides its EGF-like domain. The CD44-NRG1 fusion protein thus retains the EGF-like domain of NRG1 and the ability to drive the proliferation and survival of a small group of human cancers, particularly pancreatic cancer.

[0143] When present in abnormal cells of a patient or individual, the polynucleotide fusion preferably further comprises any sequence at 5' of CD44 exon 5 and any sequence at 3' of NRG1 exon 6, but the presence of at least SEQ ID NO: 65 and 130 may be sufficient for detection of the fusion junction using a polynucleotide-based assay. Any sequence from 5' of CD44 exon 5 comprises or consists of one or all of SEQ ID NO: 61-64 (or any variant of SEQ ID NO: 61-64), and any sequence from 3' of NRG1 exon 6 comprises or consists of one or all of SEQ ID NO: 131-137 (or any variant of SEQ ID NO: 131-137). SLC3A2-NRG1 polynucleotide fusion

[0144] A polynucleotide fusion comprising a portion of exon 1 of SLC3A2 transcript 6 and a portion of exon 5 of NRG1 is also provided. The exon 1 of SLC3A2 is preferably an exon of a variant of the paired gene of SEQ ID NO: 103 or SEQ ID NO: 103, and the exon 5 of NRG1 is preferably an exon of a variant of the paired gene of SEQ ID NO: 129 or SEQ ID NO: 129.

[0145] Preferably, the SLC3A2 exon 1 dual gene variant has at least 85% identity with SEQ ID NO: 103, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity, while the NRG1 exon 5 dual gene variant has at least 85% identity with SEQ ID NO: 129, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity.

[0146] Preferably, the portion of exon 1 of the SLC3A2 comprises or is based on SEQ ID NO: 13, and its dual gene variant has at least 85% identity with SEQ ID NO: 13, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. The portion of exon 5 of NRG1 in the fusion with SLC3A2 preferably comprises or includes the sequence as in SEQ ID NO: 14, and its dual gene variant has at least 85% identity with SEQ ID NO: 14, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, the portion of exon 1 of the SLC3A2 comprises or is composed 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: 13, and includes at least the nucleic acid at position 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, or 40, or all of the nucleic acids in SEQ ID NO: 13, and at least includes the nucleic acid at position 53. More preferably, a portion of exon 1 of the SLC3A2 comprises or is based on SEQ ID NO: 13 or its dual gene variant. Such short polynucleotide sequences are particularly advantageous for detecting the presence of large polynucleotide fusions between SLC3A2 and NRG1 and for determining whether such fusions are oncogenic fusions containing an EGF-like domain of NRG1 within a reading frame.

[0147] Alternatively, the portion of exon 1 of SLC3A2 comprises or is composed of SEQ ID NO: 103 (or a variant of the pair gene of SEQ ID NO: 103), including at least the nucleic acid at position 552. Preferably, the portion of exon 1 of SLC3A2 comprises or is composed of 2 to about 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids derived from SEQ ID NO: 103 or its pair gene variants, including at least the nucleic acid at position 552. 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, or 40, or all of the nucleic acids of SEQ ID NO: 103, and shall include at least the nucleic acid at position 552. In this alternative example, a portion of exon 1 of SLC3A2 preferably comprises or is based on SEQ ID NO: 103 or its dual gene variant. Preferably, the portion of exon 5 of NRG1 in the fusion with said SLC3A2 comprises 2 to about 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from SEQ ID NO: 157 or its dual gene variants, and consists of 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 or all of the nucleic acids from SEQ ID NO: 157, and includes at least the nucleic acid at position 1.

[0148] Preferably, any SLC3A2-NRG1 polynucleotide fusion provided herein is a fusion of a reading frame matching SLC3A2 and NRG1. More preferably, the fusion is a fusion of a reading frame matching a portion of exon 1 or exon 1 of transcript 6 of SLC3A2 and a portion of exon 5 or exon 5 of NRG1. The fusion of the reading frame is preferably a fusion of SEQ ID NO: 15 or its dual gene variant, and the dual gene variant has at least 85% identity with SEQ ID NO: 15, preferably at least 90%, 92%, 94%, 96% or even 98% identity.

[0149] In an alternative preferred embodiment, the polynucleotide comprising a portion of exon 1 of SLC3A2 fused to a portion of exon 5 of NRG1 comprises about 10, about 20, about 30, or up to about 40 or even all of the 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 from SEQ ID NO: 15, and at least includes the nucleic acids at positions 53 and 54. SEQ ID NO: 15 includes a junction between SLC3A2 and NRG1, particularly between a nucleic acid originating from position 53 of SLC3A2 and a nucleic acid originating from position 54 of NRG1. Preferably, the polynucleotide comprising a portion of exon 1 of SLC3A2 and a portion of exon 5 of NRG1 has the polynucleotide sequence of SEQ ID NO: 15 or a variant thereof.

[0150] In a preferred embodiment, a polynucleotide according to SEQ ID NO: 15 is provided, or a polynucleotide comprising about 20, about 30, about 40 or all of the consecutive nucleic acids from SEQ ID NO: 15, preferably including 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 of the nucleic acids from SEQ ID NO: 15, and preferably includes at least the nucleic acids at positions 53 and 54.

[0151] Preferably, the polynucleotide comprising a portion of exon 1 (or a variant thereof) of SLC3A2 transcript 6 fused to a portion of exon 5 (or a variant thereof) of NRG1 is a portion of a longer polynucleotide that further comprises or encodes an EGF-like domain of NRG1. Abnormal cell lines containing polynucleotide fusions involving said SLC3A2 or expressing the polypeptide fusion comprise or encode an EGF-like domain of NRG1. For rapid detection, diagnosis, or identification purposes, it is sufficient to demonstrate that the fusion junction between said SLC3A2 and NRG1 is frame-compliant and occurs at a location where the resulting fusion product, nucleic acid, or protein comprises an EGF-like domain of NRG1. The EGF-like domain is preferably an EGF-like domain of SEQ ID NO: 163 or its dual gene variant and has at least 85% identity with SEQ ID NO: 163, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity with it.

[0152] Preferably, a portion of exon 1 (or its counterpart variant) of SLC3A2 transcript 6 is located at the 5' position of exon 5 (or its counterpart variant) of NRG1. This alignment at the nucleic acid level results in the fusion polypeptide product containing the N-terminus of SLC3A2 and the C-terminus of NRG1. Furthermore, the SLC3A2-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 SLC3A2, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, wherein the NRG1 portion also provides its EGF-like domain. The SLC3A2-NRG1 fusion protein thus retains the EGF-like domain of NRG1 and its ability to drive the proliferation and survival of a small group of human cancers, including lung cancer or adenocarcinoma, especially lung adenocarcinoma.

[0153] When present in abnormal cells of a patient or individual, the SCL3A2-NRG1 polynucleotide fusion preferably further comprises any sequence at 3' of exon 5 of NRG1, but the presence of at least SEQ ID NO: 103 and 129 may be sufficient for detection of the fusion junction using a polynucleotide-based assay. Any sequence from 3' of exon 5 of NRG1 comprises or consists of one or all of SEQ ID NO: 130-137 (or any paired gene variant of SEQ ID NO: 130-137).

[0154] Furthermore, a polynucleotide fusion comprising a portion of exon 2 of SLC3A2 transcript 3 and a portion of exon 6 of NRG1 is provided. The exon 2 of SLC3A2 is preferably an exon of a variant of the paired gene of SEQ ID NO: 457 or SEQ ID NO: 457, and the exon 6 of NRG1 is preferably an exon of a variant of the paired gene of SEQ ID NO: 130 or SEQ ID NO: 130.

[0155] Preferably, the SLC3A2 exon 2 dual gene variant has at least 85% identity with SEQ ID NO: 457, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity, while the NRG1 exon 6 dual gene variant has at least 85% identity with SEQ ID NO: 130, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity.

[0156] Preferably, the portion of exon 2 of the SLC3A2 comprises or conforms to SEQ ID NO: 452, and its dual gene variant has at least 85% identity with SEQ ID NO: 452, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. The portion of exon 6 of NRG1 in the fusion with SLC3A2 preferably comprises or conforms to the sequence of SEQ ID NO: 453, and its dual gene variant has at least 85% identity with SEQ ID NO: 453, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, the exon 2 portion of SLC3A2 comprises or consists of up to 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids from SEQ ID NO: 452, and includes at least the nucleic acid at position 93. 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, or 40, and includes at least the nucleic acid at position 93. More preferably, the exon 2 portion of SLC3A2 comprises or is based on SEQ ID NO: 452 or its dual gene variant. These short polynucleotide sequences are particularly useful for detecting the existence of large polynucleotide fusions between SLC3A2 and NRG1 and for determining whether such fusions are oncogenic fusions containing the EGF-like domain of NRG1 within their reading frames.

[0157] Alternatively, the portion of exon 2 of SLC3A2 comprises or is composed of SEQ ID NO: 457 (or a variant of the pair gene of SEQ ID NO: 457), including at least the nucleic acid at position 93. Preferably, the portion of exon 2 of SLC3A2 comprises or is composed of 2 to about 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids derived from SEQ ID NO: 457 or its pair gene variant, and includes at least the nucleic acid at position 93. 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, or 40, or all of the nucleic acids specified in SEQ ID NO: 39, and shall include at least the nucleic acid at position 457. In this alternative example, a portion of exon 2 of SLC3A2 preferably comprises or is based on SEQ ID NO: 457 or its dual gene variant. Preferably, the portion of exon 6 of NRG1 in the fusion with SLC3A2 transcript 3 comprises 2 to about 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from SEQ ID NO: 130 or its dual gene variant, or is composed of such nucleic acids, and includes 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 or all of the nucleic acids from SEQ ID NO: 130, and includes at least the nucleic acid at position 1.

[0158] Preferably, any SLC3A2-NRG1 polynucleotide fusion provided herein is a fusion of a reading frame matching SLC3A2 and NRG1. More preferably, the fusion is a fusion of a reading frame matching a portion of exon 2 or exon 2 of transcript 3 of SLC3A2 and a portion of exon 6 or exon 6 of NRG1. The fusion of the reading frame is preferably a fusion of SEQ ID NO: 454 or its dual gene variant, and the dual gene variant has at least 85% identity with SEQ ID NO: 454, preferably at least 90%, 92%, 94%, 96% or even 98% identity.

[0159] In an alternative preferred embodiment, the polynucleotide comprising a portion of exon 2 of SLC3A2 fused to a portion of exon 6 of NRG1 comprises about 10, about 20, about 30, or up to about 40 or even all of the 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, or 40 of the nucleic acids from SEQ ID NO: 454, and at least includes the nucleic acids at positions 93 and 94. SEQ ID NO: 454 includes a junction between SLC3A2 and NRG1, particularly a junction located between a nucleic acid originating from position 93 of SLC3A2 and a nucleic acid originating from position 94 of NRG1. Preferably, the polynucleotide comprising a portion of exon 2 of SLC3A2 and a portion of exon 6 of NRG1 has the polynucleotide sequence of SEQ ID NO: 454 or a variant thereof.

[0160] In a preferred embodiment, a polynucleotide according to SEQ ID NO: 454 is provided, or a polynucleotide comprising about 20, about 30, about 40 or all of the consecutive nucleic acids from SEQ ID NO: 454, preferably including 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 of the nucleic acids from SEQ ID NO: 454, and preferably includes at least the nucleic acids at positions 93 and 94.

[0161] Preferably, the polynucleotide comprising a portion of exon 2 (or a variant thereof) of SLC3A2 transcript 3 fused to a portion of exon 6 (or a variant thereof) of NRG1 is a portion of a longer polynucleotide that further comprises or encodes an EGF-like domain of NRG1. Abnormal cell lines containing polynucleotide fusions involving said SLC3A2 or expressing the polypeptide fusion comprise or encode an EGF-like domain of NRG1. For rapid detection, diagnosis, or identification purposes, it is sufficient to demonstrate that the fusion junction between said SLC3A2 and NRG1 is frame-compliant and occurs at a location where the resulting fusion product, nucleic acid, or protein comprises an EGF-like domain of NRG1. The EGF-like domain is preferably an EGF-like domain of SEQ ID NO: 163 or its dual gene variant and has at least 85% identity with SEQ ID NO: 163, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity with it.

[0162] Preferably, a portion of exon 2 (or its counterpart variant) of SLC3A2 transcript 3 is located at the 5' of exon 6 (or its counterpart variant) of NRG1. This nucleotide alignment results in the fusion polypeptide product containing the N-terminus of SLC3A2 and the C-terminus of NRG1. Furthermore, the SLC3A2-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 SLC3A2, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, wherein the NRG1 portion also provides its EGF-like domain. The CADM1-NRG1 fusion protein thus retains the EGF-like domain of NRG1 and its ability to drive the proliferation and survival of a small group of human cancers, including lung cancer or adenocarcinoma, especially lung adenocarcinoma.

[0163] When present in abnormal cells of a patient or individual, the SCL3A2-NRG1 polynucleotide fusion preferably further comprises any sequence at 3' of exon 6 of NRG1, but the presence of at least SEQ ID NO: 457 and 130 may be sufficient for detection of the fusion junction using a polynucleotide-based assay. Any sequence from 3' of exon 6 of NRG1 comprises or consists of one or all of SEQ ID NO: 131-137 (or any variant of the paired gene of SEQ ID NO: 131-137). VTCN1-NRG1 polynucleotide fusion

[0164] A polynucleotide fusion comprising a portion of exon 2 of VTCN1 and a portion of exon 2 of NRG1 is also provided. The exon 2 of VTCN1 is preferably an exon of the opposite gene variant of SEQ ID NO: 169 or SEQ ID NO: 169, and the exon 2 of NRG1 is preferably an exon of the opposite gene variant of SEQ ID NO: 126 or SEQ ID NO: 126.

[0165] Preferably, the VTCN1 exon 2 dual gene variant has at least 85% identity with SEQ ID NO: 169, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity, while the NRG1 exon 2 dual gene variant has at least 85% identity with SEQ ID NO: 126, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity.

[0166] Preferably, the exon 2 portion of VTCN1 comprises or is based on SEQ ID NO: 164, and its dual gene variant has at least 85% identity with SEQ ID NO: 164, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. The exon 2 portion of NRG1 in the fusion with VTCN1 preferably comprises or includes the sequence as in SEQ ID NO: 165, and its dual gene variant has at least 85% identity with SEQ ID NO: 165, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, the exon 2 portion of VTCN1 comprises or is composed of up to 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids from SEQ ID NO: 164, and includes 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, or 40, or all of the nucleic acids of SEQ ID NO: 164, and at least include the nucleic acid at position 65. More preferably, the exon 2 portion of VTCN1 contains or is based on SEQ ID NO: 164 or its dual gene variant. Such short polynucleotide sequences are particularly useful for detecting the presence of large polynucleotide fusions between VTCN1 and NRG1 and for determining whether such fusions are oncogenic fusions containing an EGF-like domain of NRG1 within a reading frame.

[0167] Preferably, any VTCN1-NRG1 polynucleotide fusion provided herein is a fusion of a reading frame matching VTCN1 and NRG1. More preferably, the fusion is a fusion of a reading frame matching VTCN1 exon 2 or a portion of exon 2 and NRG1 exon 2 or a portion of exon 2. The fusion of the reading frame matching is preferably a fusion of SEQ ID NO: 166 or its dual gene variant, and the dual gene variant has at least 85% identity with SEQ ID NO: 166, preferably at least 90%, 92%, 94%, 96% or even 98% identity.

[0168] In an alternative preferred embodiment, the polynucleotide comprising a portion of VTCN1 exon 2 fused to a portion of NRG1 exon 2 comprises about 10, about 20, about 30, or up to about 40 or even all of the 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 from SEQ ID NO: 166, and at least includes the nucleic acids at positions 65 and 66. SEQ ID NO: 166 includes a junction between VTCN1 and NRG1, particularly between a nucleic acid originating from position 65 of VTCN1 and a nucleic acid originating from position 66 of NRG1. Preferably, the polynucleotide comprising a portion of exon 2 of VTCN1 and a portion of exon 2 of NRG1 has the polynucleotide sequence of SEQ ID NO: 166 or a variant thereof. Preferably, the portion of exon 2 of NRG1 in the fusion with VTCN1 comprises or consists of 2 to 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids from SEQ ID NO: 126 or a variant thereof, and includes 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, or 40 of the SEQ ID NO: 126, or all of them, and must include at least the nucleic acid at position 1.

[0169] In a preferred embodiment, a polynucleotide according to SEQ ID NO: 166 is provided, or a polynucleotide comprising about 20, about 30, about 40 or all of the consecutive nucleic acids from SEQ ID NO: 166, preferably including 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 of the nucleic acids from SEQ ID NO: 166, and preferably includes at least the nucleic acids at positions 65 and 66.

[0170] Preferably, the polynucleotide comprising a portion of VTCN1 exon 2 (or its counterpart variant) fused to a portion of NRG1 exon 2 (or its counterpart variant) is a portion of a longer polynucleotide that further comprises or encodes an EGF-like domain of NRG1. Abnormal cell lines comprising polynucleotide fusions involving VTCN1 or expressing the polypeptide fusion comprise or encode an EGF-like domain of NRG1. For rapid detection, diagnosis, or identification purposes, it is sufficient to demonstrate that the fusion junction between VTCN1 and NRG1 is frame-compliant and occurs at a location where the resulting fusion product, nucleic acid, or protein comprises an EGF-like domain of NRG1. The EGF-like domain is preferably the EGF-like domain of SEQ ID NO: 163 or its counterpart variant and has at least 85% identity with SEQ ID NO: 163, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0171] Preferably, a portion of exon 2 of VTCN1 (or its counterpart variant) is located at the 5' position of exon 2 of NRG1 (or its counterpart variant). This nucleotide alignment results in the 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, wherein the NRG1 portion also provides its EGF-like domain. The VTCN1-NRG1 fusion protein thus retains the EGF-like domain of NRG1 and its ability to drive the proliferation and survival of a small group of human cancers, particularly adenocarcinoma.

[0172] When present in abnormal cells of a patient or individual, the polynucleotide fusion preferably further comprises any sequence at 5' of exon 2 of VTCN1 and any sequence at 3' of exon 2 of NRG1, but the presence of at least SEQ ID NO: 169 and 126 may be sufficient for detection of the fusion junction using a polynucleotide-based assay. Any sequence from 5' of exon 2 of VTCN1 comprises or is composed of SEQ ID NO: 168 (or any variant of SEQ ID NO: 168), and any sequence from 3' of exon 2 of NRG1 comprises or is composed of one or all of SEQ ID NO: 127-137 (or any variant of SEQ ID NO: 127-137). CDH1-NRG1 polynucleotide fusion

[0173] A polynucleotide fusion comprising a portion of exon 11 of CDH1 and a portion of exon 2 of NRG1 is also provided. Exon 11 of CDH1 is preferably an exon of the opposite gene variant of SEQ ID NO: 198 or SEQ ID NO: 198, and exon 2 of NRG1 is preferably an exon of the opposite gene variant of SEQ ID NO: 126 or SEQ ID NO: 126.

[0174] When present in abnormal cells of a patient or individual, the polynucleotide fusion preferably further comprises any sequence at 5' of CDH1 exon 11 and any sequence at 3' of NRG1 exon 2, but the presence of at least SEQ ID NO: 198 and 126 may be sufficient for detection of the fusion junction using a polynucleotide-based assay. Any sequence from 5' of CDH1 exon 11 comprises or consists of one or all of SEQ ID NO: 188-197 (or any variant of SEQ ID NO: 188-197), and any sequence from 3' of NRG1 exon 2 comprises or consists of one or all of SEQ ID NO: 127-137 (or any variant of SEQ ID NO: 127-137).

[0175] Preferably, the CDH1 exon 11 dual gene variant has at least 85% identity with SEQ ID NO: 198, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity, and the NRG1 exon 2 dual gene variant has at least 85% identity with SEQ ID NO: 126, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity.

[0176] Preferably, the portion of exon 11 of CDH1 comprises or is based on SEQ ID NO: 184, and its dual gene variant has at least 85% identity with SEQ ID NO: 184, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. The portion of exon 2 of NRG1 in the fusion with CDH1 preferably comprises or includes the sequence as in SEQ ID NO: 185, and its dual gene variant has at least 85% identity with SEQ ID NO: 185, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, the portion of exon 11 of CDH1 comprises or is composed of up to 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids from SEQ ID NO: 184, and includes 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, or 40, or all of the nucleic acids of SEQ ID NO: 184, and at least includes the nucleic acid at position 119. More preferably, the portion of exon 11 of CDH1 contains or is based on SEQ ID NO: 184 or its dual gene variant. Such short polynucleotide sequences are particularly useful for detecting the presence of large polynucleotide fusions between CDH1 and NRG1 and for determining whether such fusions are oncogenic fusions containing an EGF-like domain of NRG1 within a reading frame.

[0177] Alternatively, a portion of exon 11 of CDH1 comprises or is composed of SEQ ID NO: 198 (or a variant of SEQ ID NO: 198), including at least the nucleic acid at position 146. Preferably, a portion of exon 11 of CDH1 comprises or is composed of 2 to about 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids derived from or derived from SEQ ID NO: 198 or its variants, including at least the nucleic acid at position 146. 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, or 40, or all of the nucleic acids of SEQ ID NO: 198, and shall include at least the nucleic acid at position 146. In this alternative example, a portion of exon 11 of CDH1 preferably comprises or is based on SEQ ID NO: 198 or its dual gene variant.

[0178] Preferably, any CDH1-NRG1 polynucleotide fusion provided herein is a fusion of a reading frame matching CDH1 and NRG1. More preferably, the fusion is a fusion of a reading frame matching a portion of exon 11 or exon 2 of CDH1 and a portion of exon 2 or exon 2 of NRG1. The fusion of the reading frame matching is preferably a fusion of SEQ ID NO: 186 or its dual gene variant, and the dual gene variant has at least 85% identity with SEQ ID NO: 186, preferably at least 90%, 92%, 94%, 96% or even 98% identity.

[0179] In an alternative preferred embodiment, the polynucleotide comprising a portion of CDH1 exon 11 fused to a portion of NRG1 exon 2 comprises up to 10, about 20, about 30, or up to about 40 or even all of the 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 from SEQ ID NO: 186, and at least includes the nucleic acids at positions 119 and 120. SEQ ID NO: 186 includes a junction between CDH1 and NRG1, particularly between a nucleic acid originating from position 119 of CDH1 and a nucleic acid originating from position 120 of NRG1. Preferably, the polynucleotide comprising a portion of CDH1 exon 11 and a portion of NRG1 exon 2 has the polynucleotide sequence of SEQ ID NO: 186 or a variant thereof.

[0180] In a preferred embodiment, a polynucleotide according to SEQ ID NO: 186 is provided, or a polynucleotide comprising about 20, about 30, about 40 or all of the consecutive nucleic acids from SEQ ID NO: 186, preferably including 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 of the nucleic acids from SEQ ID NO: 186, and preferably includes at least the nucleic acids at positions 119 and 120.

[0181] Preferably, the polynucleotide comprising a portion of CDH1 exon 11 (or a variant thereof) fused to a portion of NRG1 exon 2 (or a variant thereof) is a portion of a longer polynucleotide that further comprises or encodes an EGF-like domain of NRG1. Abnormal cell lines comprising polynucleotide fusions involving CDH1 or expressing the polypeptide fusion comprise or encode an EGF-like domain of NRG1. For rapid detection, diagnosis, or identification purposes, it is sufficient to demonstrate that the fusion junction between CDH1 and NRG1 is frame-compliant and occurs at a location where the resulting fusion product, nucleic acid, or protein comprises an EGF-like domain of NRG1. The EGF-like domain is preferably the EGF-like domain according to SEQ ID NO: 163 or a variant thereof and has at least 85% identity with SEQ ID NO: 163, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0182] Preferably, a portion of CDH1 exon 11 (or its paired gene variant) is located at the 5' of NRG1 exon 2 (or its paired gene variant). This nucleotide-level alignment results in the 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, wherein the NRG1 portion also provides its EGF-like domain. The CDH1-NRG1 fusion protein thus retains the EGF-like domain of NRG1 and its ability to drive the proliferation and survival of a small group of human cancers, including lung or adenocarcinoma, especially lung adenocarcinoma. CXADR-NRG1 polynucleotide fusion

[0183] A polynucleotide fusion comprising a portion of exon 1 of CXADR and a portion of exon 2 of NRG1 is also provided. Exon 1 of CXADR is preferably an exon of the opposite gene variant of SEQ ID NO: 2199 or SEQ ID NO: 219, and exon 2 of NRG1 is preferably an exon of the opposite gene variant of SEQ ID NO: 126 or SEQ ID NO: 126.

[0184] When present in abnormal cells of a patient or individual, the polynucleotide fusion preferably further comprises any sequence at the 5' of exon 1 of CXADR and any sequence at the 3' of exon 2 of NRG1, but the presence of at least SEQ ID NO: 219 and 126 may be sufficient for detection of the fusion junction using a polynucleotide-based assay. Any sequence at the 3' of exon 2 of NRG1 comprises or consists of one or all of SEQ ID NO: 127-137 (or any variant of the paired gene of SEQ ID NO: 127-137).

[0185] Preferably, the CXADR exon 1 dual gene variant has at least 85% identity with SEQ ID NO: 219, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity, and the NRG1 exon 2 dual gene variant has at least 85% identity with SEQ ID NO: 126, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity.

[0186] Preferably, the exon 1 portion of CXADR comprises or is based on SEQ ID NO: 215, and its paired gene variant has at least 85% identity with SEQ ID NO: 215, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. The exon 2 portion of NRG1 in the fusion with CXADR preferably comprises or includes the sequence as in SEQ ID NO: 216, and its paired gene variant has at least 85% identity with SEQ ID NO: 216, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, the exon 1 portion of CXADR comprises or is composed of up to 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids from SEQ ID NO: 215, and includes at least the nucleic acid at position 43. 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, or 40, or all of the nucleic acids in SEQ ID NO: 215, and at least include the nucleic acid at position 43. More preferably, a portion of exon 1 of CXADR contains or is based on SEQ ID NO: 215 or a variant thereof. Such short polynucleotide sequences are particularly useful for detecting the presence of large polynucleotide fusions between CXADR and NRG1 and for determining whether such fusions are oncogenic fusions containing an EGF-like domain of NRG1 that fits the reading frame.

[0187] Alternatively, a portion of CXADR exon 1 comprises or is composed of SEQ ID NO: 219 (or a variant of SEQ ID NO: 219), including at least the nucleic acid at position 130. Preferably, a portion of CXADR exon 1 comprises or is composed of 2 to about 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids derived from or derived from SEQ ID NO: 219 or its variants, including at least the nucleic acid at position 130. 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, or 40, or all of the nucleic acids of SEQ ID NO: 219, and shall include at least the nucleic acid at position 130. In this alternative example, a portion of exon 1 of CXADR preferably comprises or is based on SEQ ID NO: 219 or its dual gene variant.

[0188] Preferably, any CXADR-NRG1 polynucleotide fusion provided herein is a fusion of a CXADR and NRG1 frame of reference. More preferably, the fusion is a fusion of a frame of reference comprising a portion of exon 1 or exon 2 of CXADR and a portion of exon 2 or exon 2 of NRG1. The fusion of the frame of reference is preferably a fusion of SEQ ID NO: 217 or its dual gene variant, and the dual gene variant has at least 85% identity with SEQ ID NO: 217, preferably at least 90%, 92%, 94%, 96% or even 98% identity.

[0189] In an alternative preferred embodiment, the polynucleotide comprising a portion of CXADR exon 1 fused to a portion of NRG1 exon 2 comprises up to 10, about 20, about 30, or up to about 40 or even all of the 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 from SEQ ID NO: 217, and at least includes the nucleic acids at positions 43 and 44. SEQ ID NO: 217 includes a junction between CXADR and NRG1, particularly a junction between a nucleic acid originating from position 43 of CXADR and a nucleic acid originating from position 44 of NRG1. Preferably, the polynucleotide comprising a portion of exon 1 of CXADR and a portion of exon 2 of NRG1 has the polynucleotide sequence of SEQ ID NO: 217 or a variant thereof. Preferably, the portion of exon 2 of NRG1 in the fusion with CXADR comprises or consists of 2 to 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids from SEQ ID NO: 126 or a variant thereof, and includes 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, or 40 of the SEQ ID NO: 126, or all of them, and must include at least the nucleic acid at position 1.

[0190] In a preferred embodiment, a polynucleotide according to SEQ ID NO: 217 is provided, or a polynucleotide comprising about 20, about 30, about 40 or all of the consecutive nucleic acids from SEQ ID NO: 217, preferably including 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 of the nucleic acids from SEQ ID NO: 217, and preferably includes at least the nucleic acids at positions 43 and 44.

[0191] Preferably, the polynucleotide comprising a portion of CXADR exon 1 (or its counterpart variant) fused to a portion of NRG1 exon 2 (or its counterpart variant) is a portion of a longer polynucleotide that further comprises or encodes an EGF-like domain of NRG1. Abnormal cell lines comprising polynucleotide fusions involving CXADR or expressing the polypeptide fusion comprise or encode an EGF-like domain of NRG1. For rapid detection, diagnosis, or identification purposes, it is sufficient to demonstrate that the fusion junction between CXADR and NRG1 is frame-compliant and occurs at a location where the resulting fusion product, nucleic acid, or protein comprises an EGF-like domain of NRG1. The EGF-like domain is preferably the EGF-like domain according to SEQ ID NO: 163 or its counterpart variant and has at least 85% identity with SEQ ID NO: 163, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0192] Preferably, a portion of exon 1 of CXADR (or its paired gene variant) is located at the 5' position of exon 2 of NRG1 (or its paired gene variant). This nucleotide-level alignment results in the 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, wherein the NRG1 portion also provides its EGF-like domain. The CXADR-NRG1 fusion protein thus retains the EGF-like domain of NRG1 and its ability to drive the proliferation and survival of a small group of human cancers, particularly colorectal cancer. GTF2E2-NRG1 polynucleotide fusion

[0193] A polynucleotide fusion comprising a portion of exon 2 of GTF2E2 and a portion of exon 2 of NRG1 is also provided. Exon 2 of GTF2E2 is preferably an exon of the opposite gene variant of SEQ ID NO: 236 or SEQ ID NO: 236, and exon 2 of NRG1 is preferably an exon of the opposite gene variant of SEQ ID NO: 126 or SEQ ID NO: 126.

[0194] When present in abnormal cells of a patient or individual, the polynucleotide fusion preferably further comprises any sequence at 5' of exon 2 of GTF2E2 and any sequence at 3' of exon 2 of NRG1, but the presence of at least SEQ ID NO: 236 and 126 may be sufficient for detection of the fusion junction using a polynucleotide-based assay. Any sequence from 5' of exon 2 of GTF2E2 comprises or is composed of SEQ ID NO: 235 (or any variant of SEQ ID NO: 235), and any sequence from 3' of exon 2 of NRG1 comprises or is composed of one or all of SEQ ID NO: 127-137 (or any variant of SEQ ID NO: 127-137).

[0195] Preferably, the GTF2E2 exon 2 dual gene variant has at least 85% identity with SEQ ID NO: 236, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity, and the NRG1 exon 2 dual gene variant has at least 85% identity with SEQ ID NO: 126, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity.

[0196] Preferably, the exon 2 portion of GTF2E2 comprises or conforms to SEQ ID NO: 231, and its dual gene variant has at least 85% identity with SEQ ID NO: 231, more preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. The exon 2 portion of NRG1 in the fusion with GTF2E2 preferably comprises or conforms to the sequence of SEQ ID NO: 232, and its dual gene variant has at least 85% identity with SEQ ID NO: 232, more preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, the exon 2 portion of GTF2E2 comprises or consists of up to 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids from SEQ ID NO: 231, and includes at least the nucleic acid at position 141. 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: 231, and includes at least the nucleic acid at position 141. More preferably, the exon 2 portion of GTF2E2 comprises or is based on SEQ ID NO: 231 or its dual gene variant. These short polynucleotide sequences are particularly useful for detecting the existence of large polynucleotide fusions between GTF2E2 and NRG1 and for determining whether such fusions are oncogenic fusions containing an EGF-like domain of NRG1 that fits the reading frame.

[0197] Alternatively, the portion of exon 2 of GTF2E2 comprises or is composed of SEQ ID NO: 236 (or a variant of the pair gene of SEQ ID NO: 236), including at least the nucleic acid at position 170. Preferably, the portion of exon 2 of GTF2E2 comprises or is composed of 2 to about 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids derived from SEQ ID NO: 236 or its variant, including at least the nucleic acid at position 170. 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, or 40 of the nucleic acids in SEQ ID NO: 236, and at least the nucleic acid at position 170. In this alternative example, the portion of exon 2 of GTF2E2 preferably comprises or is based on SEQ ID NO: 236 or its dual gene variant. Preferably, the NRG1 exon 2 portion of the fusion with GTF2E2 comprises or consists of 2 to about 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from SEQ ID NO: 126 or its dual gene variant, and includes 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 or all of the nucleic acids from SEQ ID NO: 126, and includes at least the nucleic acid at position 1.

[0198] Preferably, any GTF2E2-NRG1 polynucleotide fusion provided herein is a fusion of a reading frame matching GTF2E2 and NRG1. More preferably, the fusion is a fusion of a reading frame matching GTF2E2 exon 2 or a portion of exon 2 and NRG1 exon 2 or a portion of exon 2. The fusion of the reading frame is preferably a fusion of SEQ ID NO: 233 or its dual gene variant, and the dual gene variant has at least 85% identity with SEQ ID NO: 233, preferably at least 90%, 92%, 94%, 96% or even 98% identity.

[0199] In an alternative preferred embodiment, the polynucleotide comprising a portion of exon 2 of GTF2E2 fused to a portion of exon 2 of NRG1 comprises up to 10, about 20, about 30, or up to about 40 or even all of the 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 from SEQ ID NO: 233, and at least includes the nucleic acids at positions 141 and 142. SEQ ID NO: 233 includes a junction between GTF2E2 and NRG1, particularly between a nucleic acid originating from position 141 of GTF2E2 and a nucleic acid originating from position 142 of NRG1. Preferably, the polynucleotide comprising a portion of exon 2 of GTF2E2 and a portion of exon 2 of NRG1 has the polynucleotide sequence of SEQ ID NO: 233 or a variant thereof.

[0200] In a preferred embodiment, a polynucleotide according to SEQ ID NO: 233 is provided, or a polynucleotide comprising about 20, about 30, about 40 or all of the consecutive nucleic acids from SEQ ID NO: 233, preferably including 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 of the nucleic acids from SEQ ID NO: 233, and preferably includes at least the nucleic acids at positions 141 and 142.

[0201] Preferably, the polynucleotide comprising a portion of exon 2 of GTF2E2 (or a variant thereof) fused to a portion of exon 2 of NRG1 (or a variant thereof) is a portion of a longer polynucleotide that further comprises or encodes an EGF-like domain of NRG1. Abnormal cell lines containing polynucleotide fusions involving GTF2E2 or expressing such polypeptide fusions comprise or encode an EGF-like domain of NRG1. For rapid detection, diagnosis, or identification purposes, it is sufficient to demonstrate that the fusion junction between GTF2E2 and NRG1 is frame-compliant and occurs at a location where the resulting fusion product, nucleic acid, or protein comprises an EGF-like domain of NRG1. The EGF-like domain is preferably an EGF-like domain of SEQ ID NO: 163 or its dual gene variant and has at least 85% identity with SEQ ID NO: 163, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity with it.

[0202] Preferably, a portion of exon 2 of GTF2E2 (or its counterpart variant) is located at the 5' position of exon 2 of NRG1 (or its counterpart variant). This nucleotide-level alignment results in the fusion polypeptide product containing the N-terminus of GTF2E2 and the C-terminus of NRG1. Furthermore, the GTF2E2-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 GTF2E2, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, wherein the NRG1 portion also provides its EGF-like domain. The GTF2E2-NRG1 fusion protein thus retains the EGF-like domain of NRG1 and its ability to drive the proliferation and survival of a small subset of human cancers, particularly (metastatic) breast cancer NOS. CSMD1-NRG1 polynucleotide fusion.

[0203] A polynucleotide fusion comprising a portion of exon 23 of CSMD1 and a portion of exon 6 of NRG1 is also provided. Exon 23 of CSMD1 is preferably an exon of the opposite gene variant of SEQ ID NO: 279 or SEQ ID NO: 279, and exon 6 of NRG1 is preferably an exon of the opposite gene variant of SEQ ID NO: 130 or SEQ ID NO: 130.

[0204] When present in abnormal cells of a patient or individual, the polynucleotide fusion preferably further comprises any sequence at 5' of exon 23 of CSMD1 and any sequence at 3' of exon 6 of NRG1, but the presence of at least SEQ ID NO: 279 and 130 may be sufficient for detection of the fusion junction using a polynucleotide-based assay. Any sequence from 5' of exon 23 of CSMD1 comprises or consists of any one or all of SEQ ID NO: 257-278 (or any variant of SEQ ID NO: 257-278), and any sequence from 3' of exon 6 of NRG1 comprises or consists of any one or all of SEQ ID NO: 131-137 (or any variant of SEQ ID NO: 131-137).

[0205] Preferably, the CSMD1 exon 23 dual gene variant has at least 85% identity with SEQ ID NO: 279, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity, and the NRG1 exon 6 dual gene variant has at least 85% identity with SEQ ID NO: 130, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity.

[0206] Preferably, the portion of exon 23 of CSMD1 comprises or is based on SEQ ID NO: 253, and its paired gene variant has at least 85% identity with SEQ ID NO: 253, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. The portion of exon 6 of NRG1 in the fusion with CSMD1 preferably comprises or is based on the sequence of SEQ ID NO: 254, and its paired gene variant has at least 85% identity with SEQ ID NO: 254, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, the portion of exon 23 of CSMD1 comprises or is composed 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: 253, and includes at least the nucleic acid at position 88. 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, or 40, or all of the nucleic acids of SEQ ID NO: 253, and at least include the nucleic acid at position 88. More preferably, the portion of exon 23 of CSMD1 contains or is based on SEQ ID NO: 253 or its dual gene variant. Such short polynucleotide sequences are particularly useful for detecting the presence of large polynucleotide fusions between CSMD1 and NRG1 and for determining whether such fusions are oncogenic fusions containing an EGF-like domain of NRG1 within a reading frame.

[0207] Alternatively, the portion of exon 23 of CSMD1 comprises or is composed of SEQ ID NO: 279 (or a variant of the pair gene of SEQ ID NO: 279), including at least the nucleic acid at position 157. Preferably, the portion of exon 23 of CSMD1 comprises or is composed of 2 to about 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids derived from or derived from SEQ ID NO: 279 or its pair gene variant, including at least the nucleic acid at position 157. 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, or 40, or all of the nucleic acids of SEQ ID NO: 279, and shall include at least the nucleic acid at position 157. In this alternative example, the portion of exon 23 of CSMD1 preferably comprises or is based on SEQ ID NO: 279 or its dual gene variant. Preferably, the NRG1 exon 6 portion of the fusion with CSMD1 comprises or consists of 2 to 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from SEQ ID NO: 130 or its dual gene variant, and includes 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 or all of the nucleic acids from SEQ ID NO: 130, and includes at least the nucleic acid at position 1.

[0208] Preferably, any CSMD1-NRG1 polynucleotide fusion provided herein is a fusion of a reading frame matching CSMD1 and NRG1. More preferably, the fusion is a fusion of a reading frame matching a portion of exon 23 or exon 6 of CSMD1 and a portion of exon 6 or exon 6 of NRG1. The fusion of the reading frame matching is preferably a fusion of SEQ ID NO: 255 or its dual gene variant, and the dual gene variant has at least 85% identity with SEQ ID NO: 255, preferably at least 90%, 92%, 94%, 96% or even 98% identity.

[0209] In an alternative preferred embodiment, the polynucleotide comprising a portion of CSMD1 exon 23 fused to a portion of NRG1 exon 6 comprises about 10, about 20, about 30, or up to about 40 or even all of the 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 from SEQ ID NO: 255, and at least includes the nucleic acids at positions 88 and 89. SEQ ID NO: 255 includes a junction between CSMD1 and NRG1, particularly between a nucleic acid originating from position 88 of CSMD1 and a nucleic acid originating from position 89 of NRG1. Preferably, the polynucleotide comprising a portion of exon 23 of CSMD1 and a portion of exon 6 of NRG1 has the polynucleotide sequence of SEQ ID NO: 255 or a variant thereof.

[0210] In a preferred embodiment, a polynucleotide according to SEQ ID NO: 255 is provided, or a polynucleotide comprising about 20, about 30, about 40 or all of the consecutive nucleic acids from SEQ ID NO: 255, preferably including 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 of the nucleic acids from SEQ ID NO: 255, and preferably includes at least the nucleic acids at positions 88 and 89.

[0211] Preferably, the polynucleotide comprising a portion of CSMD1 exon 23 (or a variant thereof) fused to a portion of NRG1 exon 6 (or a variant thereof) is a portion of a longer polynucleotide that further comprises or encodes an EGF-like domain of NRG1. Abnormal cell lines comprising polynucleotide fusions involving CSMD1 or expressing the polypeptide fusion comprise or encode an EGF-like domain of NRG1. For rapid detection, diagnosis, or identification purposes, it is sufficient to demonstrate that the fusion junction between CSMD1 and NRG1 is frame-compliant and occurs at a location where the resulting fusion product, nucleic acid, or protein comprises an EGF-like domain of NRG1. The EGF-like domain is preferably the EGF-like domain according to SEQ ID NO: 163 or a variant thereof and has at least 85% identity with SEQ ID NO: 163, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0212] Preferably, a portion of exon 23 of CSMD1 (or its paired gene variant) is located at the 5' position of exon 6 of NRG1 (or its paired gene variant). This nucleotide-level alignment results in the fusion polypeptide product containing the N-terminus of CSMD1 and the C-terminus of NRG1. Furthermore, the CSMD1-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 CSMD1, and the portion from the junction to the C-terminus is a polypeptide sequence from NRG1, wherein the NRG1 portion also provides its EGF-like domain. The CSMD1-NRG1 fusion protein thus retains the EGF-like domain of NRG1 and its ability to drive the proliferation and survival of a small group of human cancers, particularly adenocarcinoma, and more particularly pancreatic ductal adenocarcinoma. PTN-NRG1 polynucleotide fusion

[0213] A polynucleotide fusion comprising a portion of exon 4 of PTN and a portion of exon 2 of NRG1 is also provided. Exon 4 of PTN is preferably an exon of the opposite gene variant of SEQ ID NO: 318 or SEQ ID NO: 318, and exon 2 of NRG1 is preferably an exon of the opposite gene variant of SEQ ID NO: 126 or SEQ ID NO: 126.

[0214] When present in abnormal cells of a patient or individual, the polynucleotide fusion preferably further comprises any sequence at 5' of exon 4 of PTN and any sequence at 3' of exon 2 of NRG1, but the presence of at least SEQ ID NO: 318 and 126 may be sufficient for detection of the fusion junction using a polynucleotide-based assay. Any sequence from 5' of exon 4 of PTN comprises or consists of any one or all of SEQ ID NO: 315-317 (or any variant of the paired gene of SEQ ID NO: 315-317), and any sequence from 3' of exon 2 of NRG1 comprises or consists of any one or all of SEQ ID NO: 127-137 (or any variant of the paired gene of SEQ ID NO: 127-137).

[0215] Preferably, the PTN exon 4 dual gene variant has at least 85% identity with SEQ ID NO: 318, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity, while the NRG1 exon 2 dual gene variant has at least 85% identity with SEQ ID NO: 126, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity.

[0216] Preferably, the portion of exon 4 of PTN comprises or is based on SEQ ID NO: 311, and its dual gene variant has at least 85% identity with SEQ ID NO: 311, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. The portion of exon 2 of NRG1 in the fusion with PTN preferably comprises or is based on the sequence of SEQ ID NO: 312, and its dual gene variant has at least 85% identity with SEQ ID NO: 312, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, the portion of exon 4 of PTN comprises or is composed 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: 311, and includes at least the nucleic acid at position 102. 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, or 40, or all of the nucleic acids of SEQ ID NO: 311, and at least includes the nucleic acid at position 102. More preferably, the portion of exon 4 of PTN contains or is based on SEQ ID NO: 311 or its dual gene variant. Such short polynucleotide sequences are particularly useful for detecting the presence of large polynucleotide fusions between PTN and NRG1 and for determining whether such fusions are oncogenic fusions containing an EGF-like domain of NRG1 that fits the reading frame.

[0217] Alternatively, the portion of PTN exon 4 comprises or is composed of SEQ ID NO: 318 (or a variant of SEQ ID NO: 318), including at least the nucleic acid at position 162. Preferably, the portion of PTN exon 4 comprises or is composed of 2 to about 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids derived from or composed of SEQ ID NO: 318 or its variant, including at least the nucleic acid at position 162. 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, or 40, or all of the nucleic acids of SEQ ID NO: 318, and shall include at least the nucleic acid at position 162. In this alternative example, the portion of PTN exon 4 preferably comprises or is based on SEQ ID NO: 318 or its dual gene variant. Preferably, the NRG1 exon 2 portion of the fusion with PTN comprises or consists of 2 to about 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from SEQ ID NO: 126 or its dual gene variant, and includes 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 or all of the nucleic acids from SEQ ID NO: 126, and includes at least the nucleic acid at position 1.

[0218] Preferably, any PTN-NRG1 polynucleotide fusion provided herein is a fusion of a PTN and an NRG1 frame of reference. More preferably, the fusion is a fusion of a frame of reference containing a portion of exon 4 or exon 2 of PTN and a portion of exon 2 or exon 2 of NRG1. The fusion of the frame of reference is preferably a fusion of SEQ ID NO: 313 or its dual gene variant, and the dual gene variant has at least 85% identity with SEQ ID NO: 313, preferably at least 90%, 92%, 94%, 96% or even 98% identity.

[0219] In an alternative preferred embodiment, the polynucleotide comprising a portion of PTN exon 4 fused to a portion of NRG1 exon 2 comprises up to 10, about 20, about 30, or up to about 40 or even all of the 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 from SEQ ID NO: 313, and at least includes the nucleic acids at positions 102 and 103. SEQ ID NO: 313 includes a junction between PTN and NRG1, particularly between a nucleic acid originating from position 102 of PTN and a nucleic acid originating from position 103 of NRG1. Preferably, the polynucleotide comprising a portion of exon 4 of PTN and a portion of exon 2 of NRG1 has the polynucleotide sequence of SEQ ID NO: 313 or a variant thereof.

[0220] In a preferred embodiment, a polynucleotide according to SEQ ID NO: 313 is provided, or a polynucleotide comprising about 20, about 30, about 40 or all of the consecutive nucleic acids from SEQ ID NO: 313, preferably including 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 of the nucleic acids from SEQ ID NO: 313, and preferably includes at least the nucleic acids at positions 102 and 103.

[0221] Preferably, the polynucleotide comprising a portion of PTN exon 4 (or a variant thereof) fused to a portion of NRG1 exon 2 (or a variant thereof) is a portion of a longer polynucleotide that further comprises or encodes an EGF-like domain of NRG1. Abnormal cell lines comprising polynucleotide fusions involving PTN or expressing the polypeptide fusion comprise or encode an EGF-like domain of NRG1. For rapid detection, diagnosis, or identification purposes, it is sufficient to demonstrate that the fusion junction between PTN and NRG1 is frame-compliant and occurs at a location where the resulting fusion product, nucleic acid, or protein comprises an EGF-like domain of NRG1. The EGF-like domain is preferably the EGF-like domain of SEQ ID NO: 163 or a variant thereof and has at least 85% identity with SEQ ID NO: 163, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0222] Preferably, a portion of PTN exon 4 (or its paired gene variant) is located at the 5' of NRG1 exon 2 (or its paired gene variant). This nucleotide-level alignment results in the 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, wherein the NRG1 portion also provides its EGF-like domain. The PTN-NRG1 fusion protein thus retains the EGF-like domain of NRG1 and its ability to drive the proliferation and survival of a small group of human cancers, particularly adenocarcinoma, and more particularly pancreatic ductal adenocarcinoma. ST14-NRG1 polynucleotide fusion

[0223] A polynucleotide fusion comprising a portion of exon 11 of ST14 and a portion of exon 6 of NRG1 is also provided. Exon 11 of ST14 is preferably an exon of the opposite gene variant of SEQ ID NO: 342 or SEQ ID NO: 342, and exon 6 of NRG1 is preferably an exon of the opposite gene variant of SEQ ID NO: 130 or SEQ ID NO: 130.

[0224] When present in abnormal cells of a patient or individual, the polynucleotide fusion preferably further comprises any sequence at 5' of exon 11 of ST14 and any sequence at 3' of exon 6 of NRG1, but the presence of at least SEQ ID NO: 324 and 130 may be sufficient for detection of the fusion junction using a polynucleotide-based assay. Any sequence from 5' of exon 11 of ST14 comprises or consists of any one or all of SEQ ID NO: 332-341 (or any variant of SEQ ID NO: 332-341), and any sequence from 3' of exon 6 of NRG1 comprises or consists of any one or all of SEQ ID NO: 131-137 (or any variant of SEQ ID NO: 131-137).

[0225] Preferably, the ST14 exon 11 dual gene variant has at least 85% identity with SEQ ID NO: 342, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity, and the NRG1 exon 6 dual gene variant has at least 85% identity with SEQ ID NO: 130, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity.

[0226] Preferably, the portion of exon 11 of ST14 comprises or is based on SEQ ID NO: 328, and its paired gene variant has at least 85% identity with SEQ ID NO: 328, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. The portion of exon 6 of NRG1 in the fusion with ST14 preferably comprises or includes the sequence as in SEQ ID NO: 329, and its paired gene variant has at least 85% identity with SEQ ID NO: 329, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, the portion of exon 11 of ST14 comprises or is composed 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: 328, and includes 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, or 40, or all of the nucleic acids of SEQ ID NO: 328, and at least include the nucleic acid at position 95. More preferably, the portion of exon 11 of ST14 contains or is based on SEQ ID NO: 328 or its dual gene variant. Such short polynucleotide sequences are particularly useful for detecting the presence of large polynucleotide fusions between ST14 and NRG1 and for determining whether such fusions are oncogenic fusions containing an EGF-like domain of NRG1 within a reading frame.

[0227] Alternatively, a portion of exon 11 of ST14 comprises or is composed of SEQ ID NO: 342 (or a variant of SEQ ID NO: 342), including at least the nucleic acid at position 131. Preferably, a portion of exon 11 of ST14 comprises or is composed of 2 to about 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids derived from or derived from SEQ ID NO: 342 or its variants, including at least the nucleic acid at position 131. 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, or 40 of the nucleic acids in SEQ ID NO: 342, or all of them, and shall include at least the nucleic acid at position 131. In this alternative example, a portion of exon 11 of ST14 preferably comprises or is based on SEQ ID NO: 342 or its dual gene variant. Preferably, the NRG1 exon 6 portion of the fusion with ST14 comprises or consists of 2 to about 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from SEQ ID NO: 130 or its dual gene variant, and includes 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 or all of the nucleic acids from SEQ ID NO: 130, and includes at least the nucleic acid at position 1.

[0228] Preferably, any ST14-NRG1 polynucleotide fusion provided herein is a fusion of a reading frame matching ST14 and NRG1. More preferably, the fusion is a fusion of a reading frame matching a portion of exon 11 or exon 6 of ST14 and a portion of exon 6 or exon 6 of NRG1. The fusion of the reading frame matching is preferably a fusion of SEQ ID NO: 330 or its dual gene variant, and the dual gene variant has at least 85% identity with SEQ ID NO: 330, preferably at least 90%, 92%, 94%, 96% or even 98% identity.

[0229] In an alternative preferred embodiment, the polynucleotide comprising a portion of exon 11 of ST14 and a portion of exon 6 of NRG1 comprises up to 10, about 20, about 30, or up to about 40 or even all of the 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, or 40 or all of the nucleic acids from SEQ ID NO: 330, and at least includes the nucleic acids at positions 95 and 96. SEQ ID NO: 330 includes a junction between ST14 and NRG1, particularly a junction located between a nucleic acid originating from position 95 of ST14 and a nucleic acid originating from position 96 of NRG1. Preferably, the polynucleotide comprising a portion of exon 11 of ST14 and a portion of exon 6 of NRG1 has the polynucleotide sequence of SEQ ID NO: 330 or a variant thereof.

[0230] In a preferred embodiment, a polynucleotide according to SEQ ID NO: 330 is provided, or a polynucleotide comprising about 20, about 30, about 40 or all of the consecutive nucleic acids from SEQ ID NO: 330, preferably including 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 of the nucleic acids from SEQ ID NO: 330, and preferably includes at least the nucleic acids at positions 95 and 96.

[0231] Preferably, the polynucleotide comprising a portion of ST14 exon 11 (or a variant thereof) fused to a portion of NRG1 exon 6 (or a variant thereof) is a portion of a longer polynucleotide that further comprises or encodes an EGF-like domain of NRG1. Abnormal cell lines comprising polynucleotide fusions involving ST14 or expressing the polypeptide fusion comprise or encode an EGF-like domain of NRG1. For rapid detection, diagnosis, or identification purposes, it is sufficient to demonstrate that the fusion junction between ST14 and NRG1 is frame-compliant and occurs at a location where the resulting fusion product, nucleic acid, or protein comprises an EGF-like domain of NRG1. The EGF-like domain is preferably the EGF-like domain according to SEQ ID NO: 163 or a variant thereof and has at least 85% identity with SEQ ID NO: 163, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0232] Preferably, a portion of exon 11 of ST14 (or its paired gene variant) is located at the 5' of exon 6 of NRG1 (or its paired gene variant). This nucleotide-level alignment results in the fusion polypeptide product containing the N-terminus of ST14 and the C-terminus of NRG1. Furthermore, the ST14-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 ST14, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, wherein the NRG1 portion also provides its EGF-like domain. The ST14-NRG1 fusion protein thus retains the EGF-like domain of NRG1 and its ability to drive the proliferation and survival of a small group of human cancers, particularly adenocarcinoma, and more particularly pancreatic ductal adenocarcinoma. THBS1-NRG1 polynucleotide fusion

[0233] A polynucleotide fusion comprising a portion of exon 9 of THBS1 and a portion of exon 6 of NRG1 is also provided. Exon 9 of THBS1 is preferably an exon of the opposite gene variant of SEQ ID NO: 386 or SEQ ID NO: 386, and exon 6 of NRG1 is preferably an exon of the opposite gene variant of SEQ ID NO: 130 or SEQ ID NO: 130.

[0234] When present in abnormal cells of a patient or individual, the polynucleotide fusion preferably further comprises any sequence at 5' of exon 9 of THBS1 and any sequence at 3' of exon 6 of NRG1, but the presence of at least SEQ ID NO: 386 and 130 may be sufficient for detection of the fusion junction using a polynucleotide-based assay. Any sequence from 5' of exon 9 of THBS1 comprises or consists of any one or all of SEQ ID NO: 378-385 (or any variant of the paired gene of SEQ ID NO: 378-385), and any sequence from 3' of exon 6 of NRG1 comprises or consists of any one or all of SEQ ID NO: 131-137 (or any variant of the paired gene of SEQ ID NO: 131-137).

[0235] Preferably, the THBS1 exon 9 dual gene variant has at least 85% identity with SEQ ID NO: 386, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity, and the NRG1 exon 6 dual gene variant has at least 85% identity with SEQ ID NO: 130, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity.

[0236] Preferably, the portion of exon 9 of THBS1 comprises or is based on SEQ ID NO: 374, and its paired gene variant has at least 85% identity with SEQ ID NO: 374, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. The portion of exon 6 of NRG1 in the fusion with THBS1 preferably comprises or includes the sequence as in SEQ ID NO: 375, and its paired gene variant has at least 85% identity with SEQ ID NO: 375, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, the portion of exon 9 of THBS1 comprises or is composed 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: 374, and includes at least the nucleic acid at position 56. 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, or 40, or all of the nucleic acids of SEQ ID NO: 374, and at least include the nucleic acid at position 56. More preferably, the portion of exon 9 of THBS1 contains or is based on SEQ ID NO: 374 or its dual gene variant. Such short polynucleotide sequences are particularly useful for detecting the presence of large polynucleotide fusions between THBS1 and NRG1 and for determining whether such fusions are oncogenic fusions containing an EGF-like domain of NRG1 within a reading frame.

[0237] Alternatively, the portion of exon 9 of THBS1 comprises or is composed of SEQ ID NO: 386 (or a variant of the pair gene of SEQ ID NO: 386), including at least the nucleic acid at position 177. Preferably, the portion of exon 9 of THBS1 comprises or is composed of 2 to about 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids derived from or composed of SEQ ID NO: 386 or its pair gene variant, including at least the nucleic acid at position 177. 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, or 40, or all of the nucleic acids of SEQ ID NO: 386, and shall include at least the nucleic acid at position 177. In this alternative example, a portion of exon 9 of THBS1 preferably comprises or is based on SEQ ID NO: 386 or its dual gene variant. Preferably, the NRG1 exon 6 portion of the fusion with THBS1 comprises or consists of 2 to about 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from SEQ ID NO: 130 or its dual gene variant, and includes 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 or all of the nucleic acids from SEQ ID NO: 130, and includes at least the nucleic acid at position 1.

[0238] Preferably, any THBS1-NRG1 polynucleotide fusion provided herein is a fusion of a reading frame matching THBS1 and NRG1. More preferably, the fusion is a fusion of a reading frame matching THBS1 containing a portion of exon 9 or exon 6 of THBS1 and a portion of exon 6 or exon 6 of NRG1. The fusion of the reading frame matching is preferably a fusion of SEQ ID NO: 376 or its dual gene variant, and the dual gene variant has at least 85% identity with SEQ ID NO: 376, preferably at least 90%, 92%, 94%, 96%, or even 98% identity.

[0239] In an alternative preferred embodiment, the polynucleotide comprising a portion of THBS1 exon 9 fused to a portion of NRG1 exon 6 comprises about 10, about 20, about 30, or up to about 40 or even all of the 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 from SEQ ID NO: 376, and at least includes the nucleic acids at positions 56 and 57. SEQ ID NO: 376 includes a junction between THBS1 and NRG1, particularly a junction located between a nucleic acid originating from position 56 of THBS1 and a nucleic acid originating from position 57 of NRG1. Preferably, the polynucleotide comprising a portion of exon 9 of THBS1 and a portion of exon 6 of NRG1 has the polynucleotide sequence of SEQ ID NO: 376 or a variant thereof.

[0240] In a preferred embodiment, a polynucleotide according to SEQ ID NO: 376 is provided, or a polynucleotide comprising about 20, about 30, about 40 or all of the consecutive nucleic acids from SEQ ID NO: 376, preferably including 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 of the nucleic acids from SEQ ID NO: 376, and preferably includes at least the nucleic acids at positions 56 and 57.

[0241] Preferably, the polynucleotide comprising a portion of THBS1 exon 9 (or a variant thereof) fused to a portion of NRG1 exon 6 (or a variant thereof) is a portion of a longer polynucleotide that further comprises or encodes an EGF-like domain of NRG1. Abnormal cell lines comprising polynucleotide fusions involving THBS1 or expressing the polypeptide fusion comprise or encode an EGF-like domain of NRG1. For rapid detection, diagnosis, or identification purposes, it is sufficient to demonstrate that the fusion junction between THBS1 and NRG1 is frame-compliant and occurs at a location where the resulting fusion product, nucleic acid, or protein comprises an EGF-like domain of NRG1. The EGF-like domain is preferably the EGF-like domain of SEQ ID NO: 163 or a variant thereof and has at least 85% identity with SEQ ID NO: 163, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0242] Preferably, a portion of exon 9 of THBS1 (or a variant thereof) is located at the 5' position of exon 6 of NRG1 (or a variant thereof). This nucleotide-level alignment results in the 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 a polypeptide sequence from NRG1, wherein the NRG1 portion also provides its EGF-like domain. The THBS1-NRG1 fusion protein thus retains the EGF-like domain of NRG1 and its ability to drive the proliferation and survival of a small group of human cancers, particularly adenocarcinoma, and more particularly pancreatic ductal adenocarcinoma. AGRN-NRG1 polynucleotide fusion

[0243] A polynucleotide fusion comprising a portion of exon 12 of AGRN and a portion of exon 6 of NRG1 is also provided. Exon 12 of AGRN is preferably an exon of the opposite gene variant of SEQ ID NO: 416 or SEQ ID NO: 416, and exon 6 of NRG1 is preferably an exon of the opposite gene variant of SEQ ID NO: 130 or SEQ ID NO: 130.

[0244] When present in abnormal cells of a patient or individual, the polynucleotide fusion preferably further comprises any sequence at 5' of exon 12 of AGRN and any sequence at 3' of exon 6 of NRG1, but the presence of at least SEQ ID NO: 416 and 130 may be sufficient for detection of the fusion junction using a polynucleotide-based assay. Any sequence from 5' of exon 12 of AGRN comprises or consists of any one or all of SEQ ID NO: 405-415 (or any variant of SEQ ID NO: 405-415), and any sequence from 3' of exon 6 of NRG1 comprises or consists of any one or all of SEQ ID NO: 131-137 (or any variant of SEQ ID NO: 131-137).

[0245] Preferably, the AGRN exon 12 dual gene variant has at least 85% identity with SEQ ID NO: 416, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity, and the NRG1 exon 6 dual gene variant has at least 85% identity with SEQ ID NO: 130, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity.

[0246] Preferably, the portion of exon 12 of AGRN comprises or is based on SEQ ID NO: 401, and its dual gene variant has at least 85% identity with SEQ ID NO: 401, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. The portion of exon 6 of NRG1 in the fusion with AGRN preferably comprises or is based on the sequence of SEQ ID NO: 402, and its dual gene variant has at least 85% identity with SEQ ID NO: 402, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, the portion of exon 12 of AGRN comprises or is composed 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: 401, and includes at least the nucleic acid at position 106. 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, or 40, or all of the nucleic acids of SEQ ID NO: 401, and at least includes the nucleic acid at position 106. More preferably, the portion of exon 12 of AGRN contains or is based on SEQ ID NO: 401 or its dual gene variant. Such short polynucleotide sequences are particularly useful for detecting the presence of large polynucleotide fusions between AGRN and NRG1 and for determining whether such fusions are oncogenic fusions containing an EGF-like domain of NRG1 within a reading frame.

[0247] Alternatively, the portion of AGRN exon 12 comprises or is composed of SEQ ID NO: 416 (or a variant of SEQ ID NO: 416), including at least the nucleic acid at position 106. Preferably, the portion of AGRN exon 12 comprises or is composed of 2 to about 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids derived from SEQ ID NO: 416 or its variants, including at least the nucleic acid at position 106. 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, or 40, or all of the nucleic acids of SEQ ID NO: 416, and shall include at least the nucleic acid at position 106. In this alternative example, a portion of exon 12 of AGRN preferably comprises or is based on SEQ ID NO: 416 or its dual gene variant. Preferably, the NRG1 exon 6 portion of the fusion with AGRN comprises 2 to about 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from SEQ ID NO: 130 or its dual gene variant, or is composed of such nucleic acids, and includes 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 or all of the nucleic acids from SEQ ID NO: 130, and includes at least the nucleic acid at position 1.

[0248] Preferably, any AGRN-NRG1 polynucleotide fusion provided herein is a fusion of a reading frame matching AGRN and NRG1. More preferably, the fusion is a fusion of a reading frame matching AGRN containing exon 12 or a portion of exon 12 and NRG1 containing exon 6 or a portion of exon 6. The fusion of the reading frame matching is preferably a fusion of SEQ ID NO: 403 or its dual gene variant, and the dual gene variant has at least 85% identity with SEQ ID NO: 403, preferably at least 90%, 92%, 94%, 96% or even 98% identity.

[0249] In an alternative preferred embodiment, the polynucleotide comprising a portion of AGRN exon 12 fused to a portion of NRG1 exon 6 comprises up to 10, about 20, about 30, or up to about 40 or even all of the 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 from SEQ ID NO: 403, and at least includes the nucleic acids at positions 106 and 107. SEQ ID NO: 403 includes a junction between AGRN and NRG1, particularly between a nucleic acid originating from position 106 of AGRN and a nucleic acid originating from position 107 of NRG1. Preferably, the polynucleotide comprising a portion of AGRN exon 12 fused to a portion of NRG1 exon 6 has the polynucleotide sequence of SEQ ID NO: 403 or a variant thereof.

[0250] In a preferred embodiment, a polynucleotide according to SEQ ID NO: 403 is provided, or a polynucleotide comprising about 20, about 30, about 40 or all of the consecutive nucleic acids from SEQ ID NO: 403, preferably including 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 of the nucleic acids from SEQ ID NO: 403, and preferably includes at least the nucleic acids at positions 106 and 107.

[0251] Preferably, the polynucleotide comprising a portion of AGRN exon 12 (or a variant thereof) fused to a portion of NRG1 exon 6 (or a variant thereof) is a portion of a longer polynucleotide that further comprises or encodes an EGF-like domain of NRG1. Abnormal cell lines comprising polynucleotide fusions involving AGRN or expressing the polypeptide fusion comprise or encode an EGF-like domain of NRG1. For rapid detection, diagnosis, or identification purposes, it is sufficient to demonstrate that the fusion junction between AGRN and NRG1 is frame-compliant and occurs at a location in which the resulting fusion product, nucleic acid, or protein comprises an EGF-like domain of NRG1. The EGF-like domain is preferably the EGF-like domain according to SEQ ID NO: 163 or a variant thereof and has at least 85% identity with SEQ ID NO: 163, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0252] Preferably, a portion of exon 12 of AGRN (or a variant thereof) is located at the 5' position of exon 6 of NRG1 (or a variant thereof). This nucleotide-level alignment results in the 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, wherein the NRG1 portion also provides its EGF-like domain. The AGRN-NRG1 fusion protein thus retains the EGF-like domain of NRG1 and its ability to drive the proliferation and survival of a small group of human cancers, particularly adenocarcinoma, and more particularly pancreatic ductal adenocarcinoma. PVALB-NRG1 polynucleotide fusion

[0253] According to this disclosure, a polynucleotide comprising a fusion of a PVALB nucleic acid sequence (or a portion thereof) and an NRG1 nucleic acid sequence (or a portion thereof) is also provided. The fusion also includes variants of the PVALB and NRG1 nucleic acid sequences.

[0254] Preferably, the PVALB nucleic acid sequence (or a portion thereof) comprises, or is composed of, any of the pairs of SEQ ID NO: 439-444 or any of the pairs of SEQ ID NO: 439-444, and the NRG1 nucleic acid sequence (or a portion thereof) comprises, or is composed of, any of the pairs of SEQ ID NO: 125-138 or any of the pairs of SEQ ID NO: 125-138. More preferably, the PVALB nucleic acid sequence comprises, or is composed of, a portion of the pairs of SEQ ID NO: 444 or SEQ ID NO: 444, and the NRG1 nucleic acid sequence comprises, or is composed of, a portion of the pairs of SEQ ID NO: 138 or SEQ ID NO: 138. SEQ ID NO: 439-443 correspond to individual exons 1-5 of the PVALB according to NM_002854.3. SEQ ID NO: 444 corresponds to exons 1-5 of PVALB according to NM_002854.3. SEQ ID NO: 125-137 correspond to individual exons 1-13 of NRG1 according to NM_001159999. SEQ ID NO: 138 corresponds to exons 1-13 of NRG1 according to NM_001159999.

[0255] In a preferred embodiment, the PVALB nucleic acid sequence portion comprises 2 to about 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from any of SEQ ID NO: 439-444 (or the dual gene variant of any of SEQ ID NO: 439-444), while the NRG1 nucleic acid sequence portion comprises 2 to about 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from any of SEQ ID NO: 125-138 (or the dual gene variant of any of SEQ ID NO: 125-138).

[0256] A polynucleotide fusion comprising a portion of exon 4 of PVALB and a portion of exon 6 of NRG1 is also provided. Exon 4 of PVALB is preferably an exon of the opposite gene variant of SEQ ID NO: 442 or SEQ ID NO: 442, and exon 6 of NRG1 is preferably an exon of the opposite gene variant of SEQ ID NO: 130 or SEQ ID NO: 130.

[0257] When present in abnormal cells of a patient or individual, the polynucleotide fusion preferably further comprises any sequence at 5' of exon 4 of PVALB and any sequence at 3' of exon 6 of NRG1, but the presence of at least SEQ ID NO: 422 and 130 may be sufficient for detection of the fusion junction using a polynucleotide-based assay. Any sequence from 5' of exon 4 of PVALB comprises or consists of any one or all of SEQ ID NO: 439-441 (or any variant of SEQ ID NO: 439-441), and any sequence from 3' of exon 6 of NRG1 comprises or consists of any one or all of SEQ ID NO: 131-137 (or any variant of SEQ ID NO: 131-137).

[0258] Preferably, the PVALB exon 4 dual gene variant has at least 85% identity with SEQ ID NO: 442, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity, and the NRG1 exon 6 dual gene variant has at least 85% identity with SEQ ID NO: 130, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity.

[0259] Preferably, the exon 4 portion of PVALB comprises or is based on SEQ ID NO: 435, and its paired gene variant has at least 85% identity with SEQ ID NO: 435, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. The exon 6 portion of NRG1 in the fusion with PVALB preferably comprises or is based on the sequence of SEQ ID NO: 436, and its paired gene variant has at least 85% identity with SEQ ID NO: 436, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, the exon 4 portion of PVALB comprises or is composed 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: 435, and includes at least the nucleic acid at position 102. 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, or 40, or all of the nucleic acids of SEQ ID NO: 435, and at least include the nucleic acid at position 102. More preferably, the portion of exon 4 of PVALB contains or is based on SEQ ID NO: 435 or its dual gene variant. Such short polynucleotide sequences are particularly useful for detecting the presence of large polynucleotide fusions between PVALB and NRG1 and for determining whether such fusions are oncogenic fusions containing an EGF-like domain of NRG1 within a reading frame.

[0260] Alternatively, the portion of exon 4 of PVALB comprises or is composed of SEQ ID NO: 442 (or a variant of the pair gene of SEQ ID NO: 442), including at least the nucleic acid at position 110. Preferably, the portion of exon 4 of PVALB comprises or is composed of 2 to about 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids derived from or derived from SEQ ID NO: 442 or its pair gene variant, including at least the nucleic acid at position 110. 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, or 40, or all of the nucleic acids of SEQ ID NO: 442, and shall include at least the nucleic acid at position 110. In this alternative example, the portion of exon 4 of PVALB preferably comprises or is based on SEQ ID NO: 442 or its dual gene variant. Preferably, the NRG1 exon 6 portion of the fusion with PVALB comprises 2 to about 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from SEQ ID NO: 130 or its dual gene variant, or is composed of such nucleic acids, and includes 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 or all of the nucleic acids from SEQ ID NO: 130, and includes at least the nucleic acid at position 1.

[0261] Preferably, any PVALB-NRG1 polynucleotide fusion provided herein is a fusion of a PVALB and NRG1 frame of reference. More preferably, the fusion is a fusion of a frame of reference comprising exon 4 or a portion of exon 4 of PVALB and exon 6 or a portion of exon 6 of NRG1. The frame of reference fusion is preferably a fusion of SEQ ID NO: 437 or its dual gene variant, and the dual gene variant has at least 85% identity with SEQ ID NO: 437, preferably at least 90%, 92%, 94%, 96% or even 98% identity.

[0262] In an alternative preferred embodiment, the polynucleotide comprising a portion of PVALB exon 4 fused to a portion of NRG1 exon 6 comprises up to 10, about 20, about 30, or up to about 40 or even all of the 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 from SEQ ID NO: 437, and at least includes the nucleic acids at positions 102 and 103. SEQ ID NO: 437 includes a junction between PVALB and NRG1, particularly between a nucleic acid originating from position 102 of PVALB and a nucleic acid originating from position 103 of NRG1. Preferably, the polynucleotide comprising a portion of exon 4 of PVALB and a portion of exon 6 of NRG1 has the polynucleotide sequence of SEQ ID NO: 437 or a variant thereof.

[0263] Preferably, the polynucleotide comprising a portion of exon 4 of PVALB (or a variant thereof) fused to a portion of exon 6 of NRG1 (or a variant thereof) is a portion of a longer polynucleotide that further comprises or encodes an EGF-like domain of NRG1. Abnormal cell lines comprising polynucleotide fusions involving PVALB or expressing the polypeptide fusion comprise or encode an EGF-like domain of NRG1. For rapid detection, diagnosis, or identification purposes, it is sufficient to demonstrate that the fusion junction between PVALB and NRG1 is frame-compliant and occurs at a location in which the resulting fusion product, nucleic acid, or protein comprises an EGF-like domain of NRG1. The EGF-like domain is preferably the EGF-like domain according to SEQ ID NO: 163 or a variant thereof and has at least 85% identity with SEQ ID NO: 163, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0264] Preferably, a portion of exon 4 of PVALB (or a variant thereof) is located at the 5' of exon 6 of NRG1 (or a variant thereof). This nucleotide-level alignment results in the 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, wherein the NRG1 portion also provides its EGF-like domain. The PVALB-NRG1 fusion protein thus retains the EGF-like domain of NRG1 and its ability to drive the proliferation and survival of a small group of human cancers, particularly adenocarcinoma, and more particularly pancreatic ductal adenocarcinoma. APP-NRG1 polynucleotide fusion

[0265] A polynucleotide fusion comprising a portion of exon 14 of APP and a portion of exon 6 of NRG1 is also provided. Exon 14 of APP is preferably an exon of the opposite gene variant of SEQ ID NO: 501 or SEQ ID NO: 501, and exon 6 of NRG1 is preferably an exon of the opposite gene variant of SEQ ID NO: 130 or SEQ ID NO: 130.

[0266] When present in abnormal cells of a patient or individual, the polynucleotide fusion preferably further comprises any sequence at 5' of exon 14 of APP and any sequence at 3' of exon 6 of NRG1, but the presence of at least SEQ ID NO: 501 and 130 may be sufficient for detection of the fusion junction using a polynucleotide-based assay. Any sequence from 5' of exon 14 of APP comprises or consists of any one or all of SEQ ID NO: 488-500 (or any variant of SEQ ID NO: 488-500), and any sequence from 3' of exon 6 of NRG1 comprises or consists of any one or all of SEQ ID NO: 131-137 (or any variant of SEQ ID NO: 131-137).

[0267] Preferably, the APP exon 14 dual gene variant has at least 85% identity with SEQ ID NO: 501, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity, and the NRG1 exon 6 dual gene variant has at least 85% identity with SEQ ID NO: 130, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity.

[0268] Preferably, the portion of exon 14 of APP comprises or is based on SEQ ID NO: 484, and its dual gene variant has at least 85% identity with SEQ ID NO: 484, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. The portion of exon 6 of NRG1 in the fusion with APP preferably comprises or is based on the sequence of SEQ ID NO: 485, and its dual gene variant has at least 85% identity with SEQ ID NO: 485, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, the portion of exon 14 of APP comprises or is composed 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: 484, and includes at least the nucleic acid at position 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, or 40, or all of the nucleic acids of SEQ ID NO: 484, and at least include the nucleic acid at position 54. More preferably, the portion of exon 14 of APP contains or is based on SEQ ID NO: 484 or a variant thereof. Such short polynucleotide sequences are particularly useful for detecting the presence of large polynucleotide fusions between APP and NRG1 and for determining whether such fusions are oncogenic fusions containing an EGF-like domain of NRG1 that fits the reading frame.

[0269] Alternatively, the portion of APP exon 14 comprises or is composed of SEQ ID NO: 501 (or a variant of SEQ ID NO: 501), including at least the nucleic acid at position 54. Preferably, the portion of APP exon 14 comprises or is composed of 2 to about 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids derived from or composed of SEQ ID NO: 501 or its variants, including at least the nucleic acid at position 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, or 40, or all of the nucleic acids of SEQ ID NO: 501, and shall include at least the nucleic acid at position 54. In this alternative example, the portion of exon 14 of APP preferably comprises or is based on SEQ ID NO: 501 or its dual gene variant. Preferably, the NRG1 exon 6 portion of the fusion with APP comprises or consists of 2 to 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from SEQ ID NO: 130 or its dual gene variants, and includes 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 or all of the nucleic acids from SEQ ID NO: 130, and includes at least the nucleic acid at position 1.

[0270] Preferably, any APP-NRG1 polynucleotide fusion provided herein is a fusion of a reading frame matching APP and NRG1. More preferably, the fusion is a fusion of a reading frame matching APP containing exon 14 or a portion of exon 14 and NRG1 containing exon 6 or a portion of exon 6. The fusion of the reading frame matching is preferably a fusion of SEQ ID NO: 486 or its dual gene variant, and the dual gene variant has at least 85% identity with SEQ ID NO: 486, preferably at least 90%, 92%, 94%, 96% or even 98% identity.

[0271] In an alternative preferred embodiment, the polynucleotide comprising a portion of APP exon 14 fused to a portion of NRG1 exon 6 comprises about 10, about 20, about 30, or up to about 40 or even all of the 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 from SEQ ID NO: 486, and at least includes the nucleic acids at positions 54 and 55. SEQ ID NO: 486 includes a junction between APP and NRG1, particularly between a nucleic acid originating from position 54 of APP and a nucleic acid originating from position 54 of NRG1. Preferably, the polynucleotide comprising a portion of APP exon 14 fused to a portion of NRG1 exon 6 has the polynucleotide sequence of SEQ ID NO: 486 or a variant thereof.

[0272] In a preferred embodiment, a polynucleotide according to SEQ ID NO: 486 is provided, or a polynucleotide comprising about 20, about 30, about 40 or all of the consecutive nucleic acids from SEQ ID NO: 486, preferably including 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 of the nucleic acids from SEQ ID NO: 486, and preferably includes at least the nucleic acids at positions 54 and 55.

[0273] Preferably, the polynucleotide comprising a portion of APP exon 14 (or a variant thereof) fused to a portion of NRG1 exon 6 (or a variant thereof) is a portion of a longer polynucleotide that further comprises or encodes an EGF-like domain of NRG1. Abnormal cell lines comprising APP or polynucleotide fusions expressing the polypeptide fusion comprise or encode an EGF-like domain of NRG1. For rapid detection, diagnosis, or identification purposes, it is sufficient to demonstrate that the fusion junction between APP and NRG1 is frame-compliant and occurs at a location where the resulting fusion product, nucleic acid, or protein comprises an EGF-like domain of NRG1. The EGF-like domain is preferably the EGF-like domain according to SEQ ID NO: 163 or a variant thereof and has at least 85% identity with SEQ ID NO: 163, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0274] Preferably, a portion of exon 14 of APP (or its paired gene variant) is located at the 5' position of exon 6 of NRG1 (or its paired gene variant). This nucleotide-level alignment results in the fusion polypeptide product containing the N-terminus of APP and the C-terminus of NRG1. Furthermore, the APP-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 APP, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, wherein the NRG1 portion also provides its EGF-like domain. The APP-NRG1 fusion protein thus retains the EGF-like domain of NRG1 and its ability to drive the proliferation and survival of a small group of human cancers, particularly adenocarcinoma, and more particularly pancreatic ductal adenocarcinoma. WRN-NRG1 polynucleotide fusion

[0275] A polynucleotide fusion comprising a portion of exon 33 of WRN and a portion of exon 6 of NRG1 is also provided. Exon 33 of WRN is preferably an exon of the opposite gene variant of SEQ ID NO: 562 or SEQ ID NO: 562, and exon 6 of NRG1 is preferably an exon of the opposite gene variant of SEQ ID NO: 130 or SEQ ID NO: 130.

[0276] When present in abnormal cells of a patient or individual, the polynucleotide fusion preferably further comprises any sequence at 5' of WRN exon 33 and any sequence at 3' of NRG1 exon 6, but the presence of at least SEQ ID NO: 562 and 130 may be sufficient for detection of the fusion junction using a polynucleotide-based assay. Any sequence from 5' of WRN exon 33 comprises or consists of any one or all of SEQ ID NO: 530-561 (or any variant of SEQ ID NO: 530-561), and any sequence from 3' of NRG1 exon 6 comprises or consists of any one or all of SEQ ID NO: 131-137 (or any variant of SEQ ID NO: 131-137).

[0277] Preferably, the variant of the paired gene of exon 33 of WRN has at least 85% identity with SEQ ID NO: 562, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity, and the variant of the paired gene of exon 6 of NRG1 has at least 85% identity with SEQ ID NO: 130, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity.

[0278] Preferably, the portion of exon 33 of the WRN comprises or is based on SEQ ID NO: 526, and its dual gene variant has at least 85% identity with SEQ ID NO: 526, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. The portion of exon 6 of NRG1 in the fusion with WRN preferably comprises or is based on the sequence of SEQ ID NO: 527, and its dual gene variant has at least 85% identity with SEQ ID NO: 527, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, the portion of exon 33 of the WRN comprises or is composed 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: 526, and includes at least the nucleic acid at position 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, or 40, or all of the nucleic acids of SEQ ID NO: 526, and at least include the nucleic acid at position 96. More preferably, the portion of exon 33 of WRN contains or is based on SEQ ID NO: 526 or a variant of its dual gene. Such short polynucleotide sequences are particularly useful for detecting the presence of large polynucleotide fusions between WRN and NRG1 and for determining whether such fusions are oncogenic fusions containing an EGF-like domain of NRG1 within a reading frame.

[0279] Alternatively, the portion of WRN exon 33 comprises or is composed of SEQ ID NO: 562 (or a variant of SEQ ID NO: 562), including at least the nucleic acid at position 163. Preferably, the portion of WRN exon 33 comprises or is composed of 2 to about 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids derived from SEQ ID NO: 562 or its variants, including at least the nucleic acid at position 163. 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, or 40, or all of the nucleic acids of SEQ ID NO: 562, and shall include at least the nucleic acid at position 163. In this alternative example, the portion of WRN exon 33 preferably comprises or is based on SEQ ID NO: 562 or its dual gene variant. Preferably, the NRG1 exon 6 portion of the fusion with WRN comprises 2 to about 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from SEQ ID NO: 130 or its dual gene variant, or is composed of such nucleic acids, and includes 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 or all of the nucleic acids from SEQ ID NO: 130, and includes at least the nucleic acid at position 1.

[0280] Preferably, any WRN-NRG1 polynucleotide fusion provided herein is a fusion of a WRN and NRG1 frame of reference. More preferably, the fusion is a fusion of a frame of reference comprising exon 33 or a portion of exon 33 of WRN and exon 6 or a portion of exon 6 of NRG1. The frame of reference fusion is preferably a fusion of SEQ ID NO: 528 or its dual gene variant, and the dual gene variant has at least 85% identity with SEQ ID NO: 528, preferably at least 90%, 92%, 94%, 96% or even 98% identity.

[0281] In an alternative preferred embodiment, the polynucleotide comprising a portion of WRN exon 33 fused to a portion of NRG1 exon 6 comprises up to 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from SEQ ID NO: 528, including the 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 from SEQ ID NO: 528, and at least includes the nucleic acids at positions 96 and 97. SEQ ID NO: 528 includes a junction between WRN and NRG1, particularly a junction between a nucleic acid originating from position 96 of WRN and a nucleic acid originating from position 97 of NRG1. Preferably, the polynucleotide comprising a portion of exon 33 of WRN and a portion of exon 6 of NRG1 has the polynucleotide sequence of SEQ ID NO: 528 or a variant thereof.

[0282] In a preferred embodiment, a polynucleotide according to SEQ ID NO: 528 is provided, or a polynucleotide comprising about 20, about 30, about 40 or all of the consecutive nucleic acids from SEQ ID NO: 528, preferably including 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 from SEQ ID NO: 528, and preferably includes at least the nucleic acids at positions 96 and 97.

[0283] Preferably, the polynucleotide comprising a portion of WRN exon 33 (or a variant thereof) fused to a portion of NRG1 exon 6 (or a variant thereof) is a portion of a longer polynucleotide that further comprises or encodes an EGF-like domain of NRG1. Abnormal cell lines comprising polynucleotide fusions involving WRN or expressing the polypeptide fusion comprise or encode an EGF-like domain of NRG1. For rapid detection, diagnosis, or identification purposes, it is sufficient to demonstrate that the fusion junction between WRN and NRG1 is within a reading frame and occurs at a location in which the resulting fusion product, nucleic acid, or protein comprises an EGF-like domain of NRG1. The EGF-like domain is preferably the EGF-like domain according to SEQ ID NO: 163 or a variant thereof and has at least 85% identity with SEQ ID NO: 163, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0284] Preferably, a portion of exon 33 of WRN (or a variant thereof) is located at the 5' of exon 6 of NRG1 (or a variant thereof). This nucleotide-level alignment results in the fusion polypeptide product containing the N-terminus of WRN and the C-terminus of NRG1. Furthermore, the WRN-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 WRN, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, wherein the NRG1 portion also provides its EGF-like domain. The WRN-NRG1 fusion protein thus retains the EGF-like domain of NRG1 and its ability to drive the proliferation and survival of a small group of human cancers, particularly breast cancer. DAAM1-NRG1 polynucleotide fusion

[0285] According to this disclosure, a polynucleotide comprising a fusion of a DAAM1 nucleic acid sequence (or a portion thereof) and an NRG1 nucleic acid sequence (or a portion thereof) is also provided. The fusion also includes variants of the DAAM1 and NRG1 nucleic acid sequences.

[0286] Preferably, the DAAM1 nucleic acid sequence (or a portion thereof) comprises, or is composed of, any of the pairs of SEQ ID NO: 606-631 or any of the pairs of SEQ ID NO: 606-631, and the NRG1 nucleic acid sequence (or a portion thereof) comprises, or is composed of, any of the pairs of SEQ ID NO: 125-138 or any of the pairs of SEQ ID NO: 125-138. More preferably, the DAAM1 nucleic acid sequence comprises, or is composed of, a portion of the pairs of SEQ ID NO: 631 or SEQ ID NO: 631, and the NRG1 nucleic acid sequence comprises, or is composed of, a portion of the pairs of SEQ ID NO: 138 or SEQ ID NO: 138. SEQ ID NO: 606-630 correspond to exons 1-25 of DAAM1 according to NM_001270520.2. SEQ ID NO: 631 corresponds to exons 1-25 of DAAM1 according to NM_001270520.2. SEQ ID NO: 125-137 correspond to exons 1-13 of NRG1 according to NM_001159999.3. SEQ ID NO: 138 corresponds to exons 1-13 of NRG1 according to NM_001159999.3.

[0287] In a preferred embodiment, the DAAM1 nucleic acid sequence portion comprises 2 to about 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from any of SEQ ID NO: 606-631 (or the dual gene variant of any of SEQ ID NO: 606-631), while the NRG1 nucleic acid sequence portion comprises 2 to about 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from any of SEQ ID NO: 125-138 (or the dual gene variant of any of SEQ ID NO: 125-138).

[0288] Preferably, the DAAM1 nucleic acid sequence dual gene variant has at least 85% identity with any of SEQ ID NO: 606-631, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity; and the NRG1 nucleic acid sequence dual gene variant has at least 85% identity with any of SEQ ID NO: 125-138, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity.

[0289] Preferably, the DAAM1 nucleic acid sequence or a portion thereof is located at the 5' position of the NRG1 nucleic acid sequence or a portion thereof.

[0290] Preferably, the polynucleotide comprising the fusion of the DAAM1 nucleic acid sequence (or a portion thereof) and the NRG1 nucleic acid sequence (or a portion thereof) contains or encodes an EGF-like domain of NRG1. Abnormal cell lines containing the DAAM1-NRG1 polynucleotide fusion contain or encode an EGF-like domain of NRG1. For detection, diagnosis, or identification purposes, it is sufficient to demonstrate that the fusion junction between DAAM1 and NRG1 is within a reading frame and occurs at a location that would allow the resulting fused nucleic acid to encode an EGF-like domain of NRG1. The EGF-like domain is preferably the EGF-like domain of SEQ ID NO: 163 or its counterpart variant and has at least 85% identity with SEQ ID NO: 163, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0291] A polynucleotide fusion comprising a portion of exon 1 of DAAM1 and a portion of exon 1 of NRG1 is also provided. Exon 1 of DAAM1 is preferably an exon of the opposite gene variant of SEQ ID NO: 606 or SEQ ID NO: 606, and exon 1 of NRG1 is preferably an exon of the opposite gene variant of SEQ ID NO: 125 or SEQ ID NO: 125.

[0292] When present in abnormal cells of a patient or individual, the polynucleotide fusion preferably further comprises any sequence at 5' of exon 1 of DAAM1 and any sequence at 3' of exon 1 of NRG1, but the presence of at least SEQ ID NO: 606 and 125 may be sufficient for detection of the fusion junction using a polynucleotide-based assay. Any sequence from 5' of exon 1 of DAAM1 comprises or is composed of SEQ ID NO: 606 (or any variant of SEQ ID NO: 606), and any sequence from 3' of exon 1 of NRG1 comprises or is composed of one or all of SEQ ID NO: 126-137 (or any variant of SEQ ID NO: 126-137).

[0293] Preferably, the DAAM1 exon 1 dual gene variant has at least 85% identity with SEQ ID NO: 606, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity, and the NRG1 exon 1 dual gene variant has at least 85% identity with SEQ ID NO: 125, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity.

[0294] Preferably, the portion of exon 1 of DAAM1 comprises or is based on SEQ ID NO: 603, and its paired gene variant has at least 85% identity with SEQ ID NO: 603, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. The portion of exon 1 of NRG1 in the fusion with DAAM1 preferably comprises or includes the sequence as in SEQ ID NO: 604, and its paired gene variant has at least 85% identity with SEQ ID NO: 604, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, the portion of exon 1 of DAAM1 comprises or is composed 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: 603, and includes 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, or 40, or all of the nucleic acids of SEQ ID NO: 603, and at least include the nucleic acid at position 75. More preferably, a portion of exon 1 of DAAM1 contains or is based on SEQ ID NO: 603 or a variant thereof. Such short polynucleotide sequences are particularly useful for detecting the presence of large polynucleotide fusions between DAAM1 and NRG1 and for determining whether such fusions are oncogenic fusions containing an EGF-like domain of NRG1 within a reading frame.

[0295] Alternatively, a portion of exon 1 of DAAM1 comprises or is composed of SEQ ID NO: 606 (or a variant of the pair gene of SEQ ID NO: 606), including at least the nucleic acid at position 102. Preferably, a portion of exon 1 of DAAM1 comprises or is composed of 2 to about 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids derived from or composed of SEQ ID NO: 606 or its variants, including at least the nucleic acid at position 102. 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, or 40, or all of the nucleic acids of SEQ ID NO: 606, and shall include at least the nucleic acid at position 102. In this alternative example, a portion of exon 1 of DAAM1 preferably comprises or is based on SEQ ID NO: 606 or its dual gene variant. Preferably, the NRG1 exon 1 portion of the fusion with DAAM1 comprises or consists of 2 to about 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from SEQ ID NO: 125 or its dual gene variants, and includes 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 or all of the nucleic acids from SEQ ID NO: 125, and includes at least the nucleic acid at position 1.

[0296] In an alternative preferred embodiment, the polynucleotide comprising a portion of DAAM1 exon 1 fused to a portion of NRG1 exon 1 comprises about 10, about 20, about 30, or up to about 40 or even all of the 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 from SEQ ID NO: 605, and at least includes the nucleic acids at positions 75 and 76. SEQ ID NO: 605 includes a junction between DAAM1 and NRG1, particularly between a nucleic acid originating from position 75 of DAAM1 and a nucleic acid originating from position 76 of NRG1. Preferably, the polynucleotide comprising a portion of exon 1 of DAAM1 and a portion of exon 1 of NRG1 has the polynucleotide sequence of SEQ ID NO: 605 or a variant thereof.

[0297] 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 is a fusion comprising exon 1 of DAAM1 (or a portion of exon 1) and exon 1 of NRG1 (or a portion of exon 1 of NRG1). The fusion is preferably a fusion of SEQ ID NO: 605 or its dual gene variant, and has at least 85% identity with SEQ ID NO: 605, preferably at least 90%, 92%, 94%, 96% or even 98% identity with it.

[0298] Preferably, a portion of DAAM1 exon 1 (or its dual gene variant) is located at the 5' position of NRG1 exon 1 (or its dual gene variant). This NRG1 protein is thus positioned downstream of the DAAM1 promoter and is expected to be transcriptionally controlled by said promoter. The resulting fusion product thus results in a non-protein fusion NRG1 protein expression and therefore contains an EGF-like domain. This leads to the ability to drive the proliferation and survival of a small group of human cancers, particularly breast cancer. ASPH-NRG1 polynucleotide fusion product

[0299] According to this disclosure, a polynucleotide comprising a fusion of an ASPH nucleic acid sequence (or a portion thereof) and an NRG1 nucleic acid sequence (or a portion thereof) is also provided. The fusion also includes variants of the ASPH and NRG1 nucleic acid sequences.

[0300] Preferably, the ASPH nucleic acid sequence (or a portion thereof) comprises, or is composed of, any of the pairs of SEQ ID NO: 637-662 or any of the pairs of SEQ ID NO: 637-662, and the NRG1 nucleic acid sequence (or a portion thereof) comprises, or is composed of, any of the pairs of SEQ ID NO: 125-138 or any of the pairs of SEQ ID NO: 125-138. More preferably, the ASPH nucleic acid sequence comprises, or is composed of, a portion of the pairs of SEQ ID NO: 662 or SEQ ID NO: 662, and the NRG1 nucleic acid sequence comprises, or is composed of, a portion of the pairs of SEQ ID NO: 138 or SEQ ID NO: 138. SEQ ID NO: 637-661 correspond to individual exons 1-25 of ASPH according to NM_001164750.2. SEQ ID NO: 662 corresponds to exons 1-25 of ASPH according to NM_001164750.2. SEQ ID NO: 125-137 correspond to individual exons 1-13 of NRG1 according to NM_001159999.3. SEQ ID NO: 138 corresponds to exons 1-13 of NRG1 according to NM_001159999.3.

[0301] In a preferred embodiment, the ASPH nucleic acid sequence portion comprises 2 to 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from any of SEQ ID NO: 637-662 (or the dual gene variant of any of SEQ ID NO: 637-662), while the NRG1 nucleic acid sequence portion comprises 2 to 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from any of SEQ ID NO: 125-138 (or the dual gene variant of any of SEQ ID NO: 125-138).

[0302] Preferably, the ASPH nucleic acid sequence dual gene variant has at least 85% identity with any of SEQ ID NO: 637-662, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity; and the NRG1 nucleic acid sequence dual gene variant has at least 85% identity with any of SEQ ID NO: 125-138, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity.

[0303] Preferably, the ASPH nucleic acid sequence or a portion thereof is located at the 5' position of the NRG1 nucleic acid sequence or a portion thereof.

[0304] Preferably, the polynucleotide comprising the ASPH nucleic acid sequence (or a portion thereof) and the NRG1 nucleic acid sequence (or a portion thereof) contains or encodes an EGF-like domain of NRG1. Abnormal cell lines containing the ASPH-NRG1 polynucleotide fusion or expressing the polypeptide fusion contain or encode an EGF-like domain of NRG1. For detection, diagnosis, or identification purposes, it is sufficient to demonstrate that the fusion junction between ASPH and NRG1 is within a reading frame and occurs at a location that would allow the resulting fusion product, nucleic acid, or protein to contain an EGF-like domain of NRG1. The EGF-like domain is preferably the EGF-like domain of SEQ ID NO: 163 or its counterpart variant and has at least 85% identity with SEQ ID NO: 163, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0305] A polynucleotide fusion comprising a portion of exon 22 of ASPH and a portion of exon 2 of NRG1 is also provided. Exon 22 of ASPH is preferably an exon of the opposite gene variant of SEQ ID NO: 658 or SEQ ID NO: 658, and exon 2 of NRG1 is preferably an exon of the opposite gene variant of SEQ ID NO: 126 or SEQ ID NO: 126.

[0306] When present in abnormal cells of a patient or individual, the polynucleotide fusion preferably further comprises any sequence at 5' of ASPH exon 22 and any sequence at 3' of NRG1 exon 2, but the presence of at least SEQ ID NO: 658 and 126 may be sufficient for detection of the fusion junction using a polynucleotide-based assay. Any sequence from 5' of ASPH exon 22 comprises one or all of SEQ ID NO: 637-657 (or any variant of SEQ ID NO: 637-657), and any sequence from 3' of NRG1 exon 2 comprises one or all of SEQ ID NO: 127-137 (or any variant of SEQ ID NO: 127-137), or is composed of the latter.

[0307] Preferably, the variant of the ASPH exon 22 has at least 85% identity with SEQ ID NO: 658, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity, and the variant of the NRG1 exon 2 has at least 85% identity with SEQ ID NO: 126, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity.

[0308] Preferably, the portion of exon 22 of ASPH comprises or is based on SEQ ID NO: 633, and its dual gene variant has at least 85% identity with SEQ ID NO: 633, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. The portion of exon 2 of NRG1 in the fusion with ASPH preferably comprises or includes the sequence as in SEQ ID NO: 634, and its dual gene variant has at least 85% identity with SEQ ID NO: 634, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, the portion of exon 22 of ASPH comprises or is composed 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: 633, and includes 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, or 40, or all of the nucleic acids of SEQ ID NO: 633, and at least include the nucleic acid at position 75. More preferably, the portion of exon 22 of ASPH contains or is based on SEQ ID NO: 633 or its dual gene variant. Such short polynucleotide sequences are particularly useful for detecting the presence of large polynucleotide fusions between ASPH and NRG1 and for determining whether such fusions are oncogenic fusions containing an EGF-like domain of NRG1 within a reading frame.

[0309] Alternatively, a portion of ASPH exon 22 comprises or is composed of SEQ ID NO: 658 (or a variant of SEQ ID NO: 658), including at least the nucleic acid at position 136. Preferably, a portion of ASPH exon 22 comprises or is composed of 2 to about 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids derived from or composed of SEQ ID NO: 658 or its variant, including at least the nucleic acid at position 136. 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, or 40, or all of the nucleic acids of SEQ ID NO: 658, and shall include at least the nucleic acid at position 136. In this alternative example, a portion of exon 22 of ASPH preferably comprises or is based on SEQ ID NO: 658 or its dual gene variant. Preferably, the NRG1 exon 2 portion of the fusion with ASPH comprises or consists of 2 to about 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from SEQ ID NO: 126 or its dual gene variant, and includes 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 or all of the nucleic acids from SEQ ID NO: 126, and includes at least the nucleic acid at position 1.

[0310] In an alternative preferred embodiment, the polynucleotide comprising a portion of ASPH exon 22 fused to a portion of NRG1 exon 2 comprises about 10, about 20, about 30, or up to about 40 or even all of the 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 from SEQ ID NO: 635, and at least includes the nucleic acids at positions 75 and 76. SEQ ID NO: 635 includes a junction between ASPH and NRG1, particularly a junction located between a nucleic acid originating from position 75 of ASPH and a nucleic acid originating from position 76 of NRG1. Preferably, the polynucleotide comprising a portion of ASPH exon 22 and a portion of NRG1 exon 2 has the polynucleotide sequence of SEQ ID NO: 635 or a variant thereof.

[0311] Preferably, any ASPH-NRG1 polynucleotide fusion provided herein is a fusion of ASPH and NRG1 within a matching reading frame. More preferably, the fusion is a fusion of a matching reading frame comprising exon 22 of ASPH or a portion of exon 22 of NRG1. The matching reading frame fusion is preferably a fusion of SEQ ID NO: 635 or its dual gene variant, and the dual gene variant has at least 85% identity with SEQ ID NO: 635, preferably at least 90%, 92%, 94%, 96%, or even 98% identity.

[0312] Preferably, a portion of ASPH exon 2 (or its counterpart variant) is located at the 5' of NRG1 exon 2 (or its counterpart variant). This nucleotide alignment results in the 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, wherein the NRG1 portion also provides its EGF-like domain. This ASPH-NRG1 fusion protein thus retains the EGF-like domain of NRG1 and its ability to drive the proliferation and survival of a small group of human cancers, particularly adenocarcinoma, and especially colorectal adenocarcinoma. NOTCH2-NRG1 Polynucleotide Fusion

[0313] A polynucleotide fusion comprising a portion of exon 6 of NOTCH2 and a portion of exon 6 of NRG1 is also provided. Exon 6 of NOTCH2 is preferably an exon of the opposite gene variant of SEQ ID NO: 700 or SEQ ID NO: 700, and exon 1 of NRG1 is preferably an exon of the opposite gene variant of SEQ ID NO: 130 or SEQ ID NO: 130.

[0314] When present in abnormal cells of a patient or individual, the polynucleotide fusion preferably further comprises any sequence at 5' of exon 6 of NOTCH2 and any sequence at 3' of exon 6 of NRG1, but the presence of at least SEQ ID NO: 700 and 130 may be sufficient for detection of the fusion junction using a polynucleotide-based assay. Any sequence from 5' of exon 6 of NOTCH2 comprises or consists of one or all of SEQ ID NO: 695-699 (or any variant of SEQ ID NO: 695-699), and any sequence from 3' of exon 6 of NRG1 comprises or consists of one or all of SEQ ID NO: 131-137 (or any variant of SEQ ID NO: 131-137).

[0315] Preferably, the variant of the pair gene of exon 6 of NOTCH2 has at least 85% identity with SEQ ID NO: 700, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity, and the variant of the pair gene of exon 6 of NRG1 has at least 85% identity with SEQ ID NO: 130, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity.

[0316] Preferably, the exon 6 portion of NOTCH2 comprises or is based on SEQ ID NO: 691, and its dual gene variant has at least 85% identity with SEQ ID NO: 691, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. The exon 6 portion of NRG1 in the fusion with NOTCH2 preferably comprises or includes a sequence as in SEQ ID NO: 692, and its dual gene variant has at least 85% identity with SEQ ID NO: 692, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, the exon 6 portion of NOTCH2 comprises or is composed 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: 691, and includes 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, or 40, or all of the nucleic acids of SEQ ID NO: 691, and at least includes the nucleic acid at position 75. More preferably, the portion of exon 6 of NOTCH2 contains or is based on SEQ ID NO: 691 or its dual gene variant. Such short polynucleotide sequences are particularly useful for detecting the presence of large polynucleotide fusions between NOTCH2 and NRG1 and for determining whether such fusions are oncogenic fusions containing an EGF-like domain of NRG1 within a reading frame.

[0317] Alternatively, the portion of exon 6 of NOTCH2 comprises or is composed of SEQ ID NO: 700 (or a variant of the pair gene of SEQ ID NO: 700), including at least the nucleic acid at position 234. Preferably, the portion of exon 6 of NOTCH2 comprises or is composed of 2 to about 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids derived from or derived from SEQ ID NO: 700 or its pair gene variant, including at least the nucleic acid at position 234. 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, or 40, or all of the nucleic acids of SEQ ID NO: 700, and shall include at least the nucleic acid at position 234. In this alternative example, the portion of exon 6 of NOTCH2 preferably comprises or is based on SEQ ID NO: 700 or its dual gene variant. Preferably, the NRG1 exon 6 portion of the fusion with NOTCH2 comprises 2 to about 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from SEQ ID NO: 130 or its dual gene variant, or is composed of such nucleic acids, and includes 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 or all of the nucleic acids from SEQ ID NO: 130, and includes at least the nucleic acid at position 1.

[0318] Preferably, any NOTCH2-NRG1 polynucleotide fusion provided herein is a fusion of a NOTCH2 and NRG1 frame of reference. More preferably, the fusion is a fusion of a frame of reference comprising exon 6 or a portion of exon 6 of NOTCH2 and exon 6 or a portion of exon 6 of NRG1. The fusion of the frame of reference is preferably a fusion of SEQ ID NO: 693 or its dual gene variant, and the dual gene variant has at least 85% identity with SEQ ID NO: 693, preferably at least 90%, 92%, 94%, 96% or even 98% identity.

[0319] In an alternative preferred embodiment, the polynucleotide comprising a portion of exon 6 of NOTCH2 and a portion of exon 6 of NRG1 comprises up to 10, about 20, about 30, or up to about 40 or even all of the 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, or 40 or all of the nucleic acids from SEQ ID NO: 693, and at least includes the nucleic acids at positions 75 and 76. SEQ ID NO: 693 includes a junction between NOTCH2 and NRG1, particularly between a nucleic acid originating from position 75 of NOTCH2 and a nucleic acid originating from position 76 of NRG1. Preferably, the polynucleotide comprising a portion of exon 6 of NOTCH2 and a portion of exon 6 of NRG1 has the polynucleotide sequence of SEQ ID NO: 693 or a variant thereof.

[0320] In a preferred embodiment, a polynucleotide according to SEQ ID NO: 693 is provided, or a polynucleotide comprising about 20, about 30, about 40 or all of the consecutive nucleic acids from SEQ ID NO: 693, preferably including 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 of the nucleic acids from SEQ ID NO: 693, and preferably includes at least the nucleic acids at positions 75 and 76.

[0321] Preferably, the polynucleotide comprising a portion of exon 6 of NOTCH2 (or a variant thereof) fused to a portion of exon 6 of NRG1 (or a variant thereof) is a portion of a longer polynucleotide that further comprises or encodes an EGF-like domain of NRG1. Abnormal cell lines comprising polynucleotide fusions involving NOTCH2 or expressing the polypeptide fusion comprise or encode an EGF-like domain of NRG1. For rapid detection, diagnosis, or identification purposes, it is sufficient to demonstrate that the fusion junction between NOTCH2 and NRG1 is within a reading frame and occurs at a location where the resulting fusion product, nucleic acid, or protein comprises an EGF-like domain of NRG1. The EGF-like domain is preferably the EGF-like domain of SEQ ID NO: 163 or a variant thereof and has at least 85% identity with SEQ ID NO: 163, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0322] Preferably, a portion of exon 6 of NOTCH2 (or its counterpart variant) is located at the 5' position of exon 6 of NRG1 (or its counterpart variant). This nucleotide-level alignment results in the 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, wherein the NRG1 portion also provides its EGF-like domain. The NOTCH2-NRG1 fusion protein thus retains the EGF-like domain of NRG1 and its ability to drive the proliferation and survival of a small group of human cancers, particularly adenocarcinoma, and more particularly pancreatic ductal adenocarcinoma. CD74-NRG1 polynucleotide fusion

[0323] A polynucleotide fusion comprising a portion of exon 2 of CD74 and a portion of exon 2 of NRG1 is also provided. Exon 2 of CD74 is preferably an exon of the opposite gene variant of SEQ ID NO: 720 or SEQ ID NO: 720, and exon 2 of NRG1 is preferably an exon of the opposite gene variant of SEQ ID NO: 126 or SEQ ID NO: 126.

[0324] When present in abnormal cells of a patient or individual, the polynucleotide fusion preferably further comprises any sequence at 5' of exon 2 of CD74 and any sequence at 3' of exon 2 of NRG1, but the presence of at least SEQ ID NO: 720 and 126 may be sufficient for detection of the fusion junction using a polynucleotide-based assay. Any sequence from 5' of exon 2 of CD74 comprises or is composed of SEQ ID NO: 719 (or any variant of SEQ ID NO: 719), and any sequence from 3' of exon 2 of NRG1 comprises or is composed of one or all of SEQ ID NO: 127-137 (or any variant of SEQ ID NO: 127-137).

[0325] Preferably, the CD74 exon 2 dual gene variant has at least 85% identity with SEQ ID NO: 720, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity, and the NRG1 exon 2 dual gene variant has at least 85% identity with SEQ ID NO: 126, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity.

[0326] Preferably, the exon 2 portion of CD74 comprises or is based on SEQ ID NO: 715, and its paired gene variant has at least 85% identity with SEQ ID NO: 715, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. The exon 2 portion of NRG1 in the fusion with CD74 preferably comprises or includes a sequence as in SEQ ID NO: 716, and its paired gene variant has at least 85% identity with SEQ ID NO: 716, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, the exon 2 portion of CD74 comprises or is composed 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: 715, and includes 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, or 40, or all of the nucleic acids of SEQ ID NO: 715, and at least include the nucleic acid at position 75. More preferably, the portion of exon 2 of CD74 contains or is based on SEQ ID NO: 715 or its dual gene variant. Such short polynucleotide sequences are particularly useful for detecting the presence of large polynucleotide fusions between CD74 and NRG1 and for determining whether such fusions are oncogenic fusions containing an EGF-like domain of NRG1 that fits the reading frame.

[0327] Alternatively, the portion of CD74 exon 2 comprises or is composed of SEQ ID NO: 720 (or a variant of SEQ ID NO: 720), including at least the nucleic acid at position 173. Preferably, the portion of CD74 exon 2 comprises or is composed of 2 to about 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids derived from SEQ ID NO: 720 or its variant, including at least the nucleic acid at position 173. 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, or 40 of the nucleic acids in SEQ ID NO: 720, or all of them, and shall include at least the nucleic acid at position 173. In this alternative example, the portion of CD74 exon 2 preferably comprises or is based on SEQ ID NO: 720 or its dual gene variant. Preferably, the NRG1 exon 2 portion of the fusion with CD74 comprises or consists of 2 to about 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from SEQ ID NO: 126 or its dual gene variant, and includes 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 or all of the nucleic acids from SEQ ID NO: 126, and includes at least the nucleic acid at position 1.

[0328] Preferably, any CD74-NRG1 polynucleotide fusion provided herein is a fusion of a reading frame matching CD74 and NRG1. More preferably, the fusion is a fusion of a reading frame matching CD74 exon 2 or a portion of exon 2 and NRG1 exon 2 or a portion of exon 2. The fusion of the reading frame is preferably a fusion of SEQ ID NO: 717 or its dual gene variant, and the dual gene variant has at least 85% identity with SEQ ID NO: 717, preferably at least 90%, 92%, 94%, 96% or even 98% identity.

[0329] In an alternative preferred embodiment, the polynucleotide comprising a portion of CD74 exon 2 fused to a portion of NRG1 exon 2 comprises about 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids from SEQ ID NO: 717, 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 from SEQ ID NO: 7, and at least includes the nucleic acids at positions 75 and 76. SEQ ID NO: 717 includes a junction between CD74 and NRG1, particularly a junction located between a nucleic acid originating from position 75 of CD74 and a nucleic acid originating from position 76 of NRG1. Preferably, the polynucleotide comprising a portion of exon 2 of CD74 and a portion of exon 2 of NRG1 has the polynucleotide sequence of SEQ ID NO: 717 or a variant thereof.

[0330] In a preferred embodiment, a polynucleotide according to SEQ ID NO: 717 is provided, or a polynucleotide comprising about 20, about 30, about 40 or all of the consecutive nucleic acids from SEQ ID NO: 717, preferably including 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 of the nucleic acids from SEQ ID NO: 717, and preferably includes at least the nucleic acids at positions 75 and 76.

[0331] Preferably, the polynucleotide comprising a portion of CD74 exon 2 (or its counterpart variant) fused to a portion of NRG1 exon 2 (or its counterpart variant) is a portion of a longer polynucleotide that further comprises or encodes an EGF-like domain of NRG1. Abnormal cell lines comprising polynucleotide fusions involving CD74 or expressing the polypeptide fusion comprise or encode an EGF-like domain of NRG1. For rapid detection, diagnosis, or identification purposes, it is sufficient to demonstrate that the fusion junction between CD74 and NRG1 is frame-compliant and occurs at a location where the resulting fusion product, nucleic acid, or protein comprises an EGF-like domain of NRG1. The EGF-like domain is preferably the EGF-like domain of SEQ ID NO: 163 or its counterpart variant and has at least 85% identity with SEQ ID NO: 163, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0332] Preferably, a portion of exon 2 of CD74 (or its counterpart variant) is located at the 5' position of exon 2 of NRG1 (or its counterpart variant). This nucleotide-level alignment results in the fusion polypeptide product containing the N-terminus of CD74 and the C-terminus of NRG1. Furthermore, the CD74-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 CD74, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, wherein the NRG1 portion also provides its EGF-like domain. The CD74-NRG1 fusion protein thus retains the EGF-like domain of NRG1 and its ability to drive the proliferation and survival of a small group of human cancers, particularly lung cancer. SDC4-NRG1 polynucleotide fusion

[0333] A polynucleotide fusion comprising a portion of exon 2 of SDC4 and a portion of exon 2 of NRG1 is also provided. The exon 2 of SDC4 is preferably an exon of a variant of the paired gene of SEQ ID NO: 746 or SEQ ID NO: 746, and the exon 2 of NRG1 is preferably an exon of a variant of the paired gene of SEQ ID NO: 126 or SEQ ID NO: 126.

[0334] Preferably, the dual gene variant of exon 2 of SDC4 has at least 85% identity with SEQ ID NO: 746, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity, while the dual gene variant of exon 2 of NRG1 has at least 85% identity with SEQ ID NO: 126, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity.

[0335] Preferably, the exon 2 portion of the SDC4 comprises or is based on SEQ ID NO: 741, and its dual gene variant has at least 85% identity with SEQ ID NO: 741, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. The exon 2 portion of the NRG1 in the fusion with SDC4 preferably comprises or includes a sequence as in SEQ ID NO: 742, and its dual gene variant has at least 85% identity with SEQ ID NO: 742, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, the exon 2 portion of the SDC4 comprises or is composed of up to 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids from SEQ ID NO: 741, and includes 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, or 40 of SEQ ID NO: 741, or all of them, and includes at least the nucleic acid at position 75. More preferably, the portion of exon 2 of SDC4 comprises or is based on SEQ ID NO: 741 or its dual gene variant. Such short polynucleotide sequences are particularly advantageous for detecting the presence of large polynucleotide fusions between SDC4 and NRG1 and for determining whether such fusions are oncogenic fusions containing an EGF-like domain of NRG1 within a reading frame.

[0336] Alternatively, the portion of exon 2 of SDC4 comprises or is composed of SEQ ID NO: 746 (or a variant of the pair gene of SEQ ID NO: 746), including at least the nucleic acid at position 139. Preferably, the portion of exon 2 of SDC4 comprises or is composed of 2 to about 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids derived from SEQ ID NO: 746 or its variants, including at least the nucleic acid at position 139. 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, or 40, or all of the nucleic acids of SEQ ID NO: 746, and shall include at least the nucleic acid at position 139. In this alternative example, the portion of exon 2 of SDC4 preferably comprises or is based on SEQ ID NO: 746 or its dual gene variant. Preferably, the NRG1 exon 2 portion of the fusion with SDC4 comprises or consists of 2 to about 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from SEQ ID NO: 126 or its dual gene variant, and includes 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 or all of the nucleic acids from SEQ ID NO: 126, and includes at least the nucleic acid at position 1.

[0337] Preferably, any SDC4-NRG1 polynucleotide fusion provided herein is a fusion of a reading frame matching SDC4 and NRG1. More preferably, the fusion is a fusion of a reading frame matching SDC4 exon 2 or a portion of exon 2 and NRG1 exon 2 or a portion of exon 2. The fusion of the reading frame matching is preferably a fusion of SEQ ID NO: 743 or its dual gene variant, and the dual gene variant has at least 85% identity with SEQ ID NO: 743, preferably at least 90%, 92%, 94%, 96% or even 98% identity.

[0338] In an alternative preferred embodiment, the polynucleotide comprising a portion of exon 2 of SDC4 fused to a portion of exon 2 of NRG1 comprises about 10, about 20, about 30, or up to about 40 or even all of the 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 from SEQ ID NO: 743, and at least includes the nucleic acids at positions 75 and 76. SEQ ID NO: 743 includes a junction between SDC4 and NRG1, particularly a junction located between a nucleic acid originating from position 75 of SDC4 and a nucleic acid originating from position 76 of NRG1. Preferably, the polynucleotide comprising a portion of exon 2 of SDC4 and a portion of exon 2 of NRG1 has the polynucleotide sequence of SEQ ID NO: 743 or a variant thereof.

[0339] In a preferred embodiment, a polynucleotide according to SEQ ID NO: 743 is provided, or a polynucleotide comprising about 20, about 30, about 40 or all of the consecutive nucleic acids from SEQ ID NO: 743, preferably including 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 of the nucleic acids from SEQ ID NO: 743, and preferably includes at least the nucleic acids at positions 75 and 76.

[0340] Preferably, the polynucleotide comprising a portion of exon 2 of SDC4 (or a variant thereof) fused to a portion of exon 2 of NRG1 (or a variant thereof) is a portion of a longer polynucleotide that further comprises or encodes an EGF-like domain of NRG1. Abnormal cell lines comprising polynucleotide fusions involving said SDC4 or expressing the polypeptide fusion comprise or encode an EGF-like domain of NRG1. For rapid detection, diagnosis, or identification purposes, it is sufficient to demonstrate that the fusion junction between SDC4 and NRG1 is frame-compliant and occurs at a location where the resulting fusion product, nucleic acid, or protein comprises an EGF-like domain of NRG1. The EGF-like domain is preferably the EGF-like domain according to SEQ ID NO: 163 or a variant thereof and has at least 85% identity with SEQ ID NO: 163, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0341] Preferably, a portion of exon 2 of SDC4 (or a variant thereof) is located at the 5' position of exon 2 of NRG1 (or a variant thereof). This alignment at the nucleic acid level results in the fusion polypeptide product containing the N-terminus of SDC4 and the C-terminus of NRG1. Furthermore, the SDC4-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 SDC4, and the portion from the junction to the C-terminus is a polypeptide sequence from NRG1, wherein the NRG1 portion also provides its EGF-like domain. The SDC4-NRG1 fusion protein thus retains the EGF-like domain of NRG1 and its ability to drive the proliferation and survival of a small group of human cancers, particularly lung cancer.

[0342] When present in abnormal cells of a patient or individual, the polynucleotide fusion preferably further comprises any sequence at 5' of exon 2 of SDC4 and any sequence at 3' of exon 2 of NRG1, but the presence of at least SEQ ID NO: 746 and 126 may be sufficient for detection of the fusion junction using a polynucleotide-based assay. Any sequence from 5' of exon 2 of SDC4 comprises or is composed of SEQ ID NO: 745 (or any variant of SEQ ID NO: 745), and any sequence from 3' of exon 2 of NRG1 comprises or is composed of one or all of SEQ ID NO: 127-137 (or any variant of SEQ ID NO: 127-137).

[0343] Furthermore, a polynucleotide fusion comprising a portion of exon 4 of SDC4 and a portion of exon 2 of NRG1 is provided. The exon 4 of SDC4 is preferably an exon of a variant of the paired gene of SEQ ID NO: 748 or SEQ ID NO: 748, and the exon 2 of NRG1 is preferably an exon of a variant of the paired gene of SEQ ID NO: 126 or SEQ ID NO: 126.

[0344] Preferably, the dual gene variant of exon 4 of SDC4 has at least 85% identity with SEQ ID NO: 748, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity, while the dual gene variant of exon 2 of NRG1 has at least 85% identity with SEQ ID NO: 126, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity.

[0345] Preferably, the portion of exon 4 of SDC4 comprises or is based on SEQ ID NO: 822, and its dual gene variant has at least 85% identity with SEQ ID NO: 822, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. The portion of exon 2 of NRG1 in the fusion with SDC4 preferably comprises or includes a sequence as in SEQ ID NO: 823, and its dual gene variant has at least 85% identity with SEQ ID NO: 823, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, the portion of exon 4 of SDC4 comprises or is composed 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: 822, and includes 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, or 40 of SEQ ID NO: 822, or all of them, and includes at least the nucleic acid at position 75. More preferably, a portion of exon 4 of SDC4 comprises or is based on SEQ ID NO: 822 or a variant thereof. Such short polynucleotide sequences are particularly advantageous for detecting the presence of large polynucleotide fusions between SDC4 and NRG1 and for determining whether such fusions are oncogenic fusions containing an EGF-like domain of NRG1 within a reading frame.

[0346] Alternatively, the portion of exon 4 of SDC4 comprises or is composed of SEQ ID NO: 748 (or a variant of the pair gene of SEQ ID NO: 748), including at least the nucleic acid at position 199. Preferably, the portion of exon 4 of SDC4 comprises or is composed of 2 to about 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids derived from SEQ ID NO: 748 or its pair gene variant, including at least the nucleic acid at position 199. 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, or 40, or all of the nucleic acids of SEQ ID NO: 748, and shall include at least the nucleic acid at position 199. In this alternative example, a portion of exon 4 of SDC4 preferably comprises or is based on SEQ ID NO: 748 or its dual gene variant. Preferably, the NRG1 exon 2 portion of the fusion with SDC4 comprises or consists of 2 to about 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from SEQ ID NO: 126 or its dual gene variant, and includes 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 or all of the nucleic acids from SEQ ID NO: 126, and includes at least the nucleic acid at position 1.

[0347] Preferably, any SDC4-NRG1 polynucleotide fusion provided herein is a fusion of a reading frame matching SDC4 and NRG1. More preferably, the fusion is a fusion of a reading frame matching SDC4 containing exon 4 or a portion of exon 4 of SDC4 and exon 2 or a portion of exon 2 of NRG1. The fusion of the reading frame matching is preferably a fusion of SEQ ID NO: 824 or its dual gene variant, and the dual gene variant has at least 85% identity with SEQ ID NO: 824, preferably at least 90%, 92%, 94%, 96% or even 98% identity.

[0348] In an alternative preferred embodiment, the polynucleotide comprising a portion of exon 4 of SDC4 and a portion of exon 2 of NRG1 comprises about 10, about 20, about 30, or up to about 40 or even all of the 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 from SEQ ID NO: 824, and at least includes the nucleic acids at positions 75 and 76. SEQ ID NO: 824 includes a junction between SDC4 and NRG1, particularly a junction located between a nucleic acid originating from position 75 of SDC4 and a nucleic acid originating from position 76 of NRG1. Preferably, the polynucleotide comprising a portion of exon 4 of SDC4 and a portion of exon 2 of NRG1 has the polynucleotide sequence of SEQ ID NO: 824 or a variant thereof.

[0349] In a preferred embodiment, a polynucleotide according to SEQ ID NO: 824 is provided, or a polynucleotide comprising about 20, about 30, about 40 or all of the consecutive nucleic acids from SEQ ID NO: 824, preferably including 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 of the nucleic acids from SEQ ID NO: 824, and preferably includes at least the nucleic acids at positions 75 and 76.

[0350] Preferably, the polynucleotide comprising a portion of exon 4 of SDC4 (or a variant thereof) fused to a portion of exon 2 of NRG1 (or a variant thereof) is a portion of a longer polynucleotide that further comprises or encodes an EGF-like domain of NRG1. Abnormal cell lines comprising polynucleotide fusions involving said SDC4 or expressing the polypeptide fusion comprise or encode an EGF-like domain of NRG1. For rapid detection, diagnosis, or identification purposes, it is sufficient to demonstrate that the fusion junction between SDC4 and NRG1 is within a reading frame and occurs at a location where the resulting fusion product, nucleic acid, or protein comprises an EGF-like domain of NRG1. The EGF-like domain is preferably the EGF-like domain according to SEQ ID NO: 163 or a variant thereof and has at least 85% identity with SEQ ID NO: 163, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0351] Preferably, a portion of exon 4 of SDC4 (or a variant thereof) is located at the 5' of exon 2 of NRG1 (or a variant thereof). This alignment at the nucleic acid level results in the fusion polypeptide product containing the N-terminus of SDC4 and the C-terminus of NRG1. Furthermore, the SDC4-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 SDC4, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, wherein the NRG1 portion also provides its EGF-like domain. The SDC4-NRG1 fusion protein thus retains the EGF-like domain of NRG1 and its ability to drive the proliferation and survival of a small group of human cancers, including lung cancer, particularly non-small cell lung cancer.

[0352] When present in abnormal cells of a patient or individual, the polynucleotide fusion preferably further comprises any sequence at 5' of exon 4 of SDC4 and any sequence at 3' of exon 2 of NRG1, but the presence of at least SEQ ID NO: 748 and 126 may be sufficient for detection of the fusion junction using a polynucleotide-based assay. Any sequence from 5' of exon 4 of SDC4 comprises or consists of one or all of SEQ ID NO: 745-747 (or any variant of the paired gene of SEQ ID NO: 745-747), and any sequence from 3' of exon 2 of NRG1 comprises or consists of one or all of SEQ ID NO: 127-137 (or any variant of the paired gene of SEQ ID NO: 127-137). SLC4A4-NRG1 polynucleotide fusion

[0353] A polynucleotide fusion comprising a portion of exon 14 of SLC4A4 and a portion of exon 6 of NRG1 is also provided. Exon 14 of SLC4A4 is preferably an exon of the opposite gene variant of SEQ ID NO: 780 or SEQ ID NO: 780, and exon 6 of NRG1 is preferably an exon of the opposite gene variant of SEQ ID NO: 130 or SEQ ID NO: 130.

[0354] When present in abnormal cells of a patient or individual, the polynucleotide fusion preferably further comprises any sequence at 5' of exon 14 of SLC4A4 and any sequence at 3' of exon 6 of NRG1, but the presence of at least SEQ ID NO: 780 and 130 may be sufficient for detection of the fusion junction using a polynucleotide-based assay. Any sequence from 5' of exon 14 of SLC4A4 comprises or consists of one or all of SEQ ID NO: 767-779 (or any variant of SEQ ID NO: 767-779), and any sequence from 3' of exon 6 of NRG1 comprises or consists of one or all of SEQ ID NO: 131-137 (or any variant of SEQ ID NO: 131-137).

[0355] Preferably, the SLC4A4 exon 14 dual gene variant has at least 85% identity with SEQ ID NO: 780, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity, and the NRG1 exon 6 dual gene variant has at least 85% identity with SEQ ID NO: 130, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity.

[0356] Preferably, the portion of exon 14 of SLC4A4 comprises or conforms to SEQ ID NO: 763, and its dual gene variant has at least 85% identity with SEQ ID NO: 763, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. The portion of exon 6 of NRG1 in the fusion with SLC4A4 preferably comprises or conforms to the sequence of SEQ ID NO: 764, and its dual gene variant has at least 85% identity with SEQ ID NO: 764, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, the portion of exon 14 of SLC4A4 comprises or consists of about 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids from SEQ ID NO: 763, and includes 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 from SEQ ID NO: 763, and includes at least the nucleic acid at position 75. More preferably, the portion of exon 14 of SLC4A4 comprises or is based on SEQ ID NO: 763 or its dual gene variant. These short polynucleotide sequences are particularly useful for detecting the existence of large polynucleotide fusions between SLC4A4 and NRG1 and for determining whether such fusions are oncogenic fusions containing the EGF-like domain of NRG1 within their reading frames.

[0357] Alternatively, a portion of exon 14 of SLC4A4 comprises or is composed of SEQ ID NO: 780 (or a variant of SEQ ID NO: 780), including at least the nucleic acid at position 272. Preferably, a portion of exon 14 of SLC4A4 comprises or is composed of 2 to about 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids derived from or derived from SEQ ID NO: 780 or its variant, including at least the nucleic acid at position 272. 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, or 40, or all of the nucleic acids of SEQ ID NO: 780, and shall include at least the nucleic acid at position 272. In this alternative example, a portion of exon 14 of SLC4A4 preferably comprises or is based on SEQ ID NO: 780 or its dual gene variant. Preferably, the NRG1 exon 6 portion of the fusion with SLC4A4 comprises, or is composed of, 2 to 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from SEQ ID NO: 130 or its dual gene variant, and includes 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 or all of the nucleic acids from SEQ ID NO: 130, and includes at least the nucleic acid at position 1.

[0358] Preferably, any SLC4A4-NRG1 polynucleotide fusion provided herein is a fusion of a reading frame matching SLC4A4 and NRG1. More preferably, the fusion is a fusion of a reading frame matching SLC4A4 exon 14 or a portion of exon 14 and NRG1 exon 6 or a portion of exon 6. The fusion of the reading frame is preferably a fusion of SEQ ID NO: 765 or its dual gene variant, and the dual gene variant has at least 85% identity with SEQ ID NO: 765, preferably at least 90%, 92%, 94%, 96% or even 98% identity.

[0359] In an alternative preferred embodiment, the polynucleotide comprising a portion of exon 14 of SLC4A4 fused to a portion of exon 6 of NRG1 comprises about 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from SEQ ID NO: 765, 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 from SEQ ID NO: 765, and at least includes the nucleic acids at positions 75 and 76. SEQ ID NO: 765 includes a junction between SLC4A4 and NRG1, particularly between a nucleic acid originating from position 75 of SLC4A4 and a nucleic acid originating from position 76 of NRG1. Preferably, the polynucleotide comprising a portion of exon 14 of SLC4A4 and a portion of exon 6 of NRG1 has the polynucleotide sequence of SEQ ID NO: 765 or a variant thereof.

[0360] In a preferred embodiment, a polynucleotide according to SEQ ID NO: 765 is provided, or a polynucleotide comprising about 20, about 30, about 40 or all of the consecutive nucleic acids from SEQ ID NO: 765, preferably including 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 of the nucleic acids from SEQ ID NO: 765, and preferably includes at least the nucleic acids at positions 75 and 76.

[0361] Preferably, the polynucleotide comprising a portion of SLC4A4 exon 14 (or a variant thereof) fused to a portion of NRG1 exon 6 (or a variant thereof) is a portion of a longer polynucleotide that further comprises or encodes an EGF-like domain of NRG1. Abnormal cell lines containing polynucleotide fusions involving SLC4A4 or expressing the polypeptide fusion comprise or encode an EGF-like domain of NRG1. For rapid detection, diagnosis, or identification purposes, it is sufficient to demonstrate that the fusion junction between SLC4A4 and NRG1 is frame-compliant and occurs at a location where the resulting fusion product, nucleic acid, or protein comprises an EGF-like domain of NRG1. The EGF-like domain is preferably an EGF-like domain of SEQ ID NO: 163 or its dual gene variant and has at least 85% identity with SEQ ID NO: 163, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity with it.

[0362] Preferably, a portion of exon 14 of SLC4A4 (or a variant thereof) is located at the 5' of exon 6 of NRG1 (or a variant thereof). This nucleotide alignment results in the fusion polypeptide product containing the N-terminus of SLC4A4 and the C-terminus of NRG1. Furthermore, the SLC4A4-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 SLC4A4, and the portion from the junction to the C-terminus is an NRG1 polypeptide sequence, wherein the NRG1 portion also provides its EGF-like domain. The SLC4A4-NRG1 fusion protein thus retains the EGF-like domain of NRG1 and its ability to drive the proliferation and survival of a small group of human cancers, particularly pancreatic cancer. ZFAT-NRG1 polynucleotide fusion

[0363] According to this disclosure, a polynucleotide comprising a fusion of a ZFAT nucleic acid sequence (or a portion thereof) and an NRG1 nucleic acid sequence (or a portion thereof) is also provided. The fusion also includes variants of the ZFAT and NRG1 nucleic acid sequences.

[0364] Preferably, the ZFAT nucleic acid sequence (or a portion thereof) comprises, or is composed of, any of the pairs of SEQ ID NO: 830-846 or any of the pairs of SEQ ID NO: 830-846, and the NRG1 nucleic acid sequence (or a portion thereof) comprises, or is composed of, any of the pairs of SEQ ID NO: 125-138 or any of the pairs of SEQ ID NO: 125-138. More preferably, the ZFAT nucleic acid sequence comprises, or is composed of, a portion of the pairs of SEQ ID NO: 846 or SEQ ID NO: 846, and the NRG1 nucleic acid sequence comprises, or is composed of, a portion of the pairs of SEQ ID NO: 138 or SEQ ID NO: 138. SEQ ID NO: 830-845 correspond to individual exons 1-16 of the ZFAT according to NM_020863.4. SEQ ID NO: 846 corresponds to exons 1-16 of ZFAT according to NM_020863.4. SEQ ID NO: 125-137 correspond to individual exons 1-13 of NRG1 according to NM_001159999.3. SEQ ID NO: 138 corresponds to exons 1-13 of NRG1 according to NM_001159999.3.

[0365] In a preferred embodiment, the ZFAT nucleic acid sequence portion comprises 2 to 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from any of SEQ ID NO: 830-846 (or the dual gene variant of any of SEQ ID NO: 830-846), while the NRG1 nucleic acid sequence portion comprises 2 to 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from any of SEQ ID NO: 125-138 (or the dual gene variant of any of SEQ ID NO: 125-138).

[0366] Preferably, the ZFAT nucleic acid sequence dual gene variant has at least 85% identity with any of SEQ ID NO: 830-846, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity; and the NRG1 nucleic acid sequence dual gene variant has at least 85% identity with any of SEQ ID NO: 125-138, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity.

[0367] Preferably, the ZFAT nucleic acid sequence or a portion thereof is located at the 5' position of the NRG1 nucleic acid sequence or a portion thereof.

[0368] Preferably, the polynucleotide comprising a ZFAT nucleic acid sequence (or a portion thereof) and an NRG1 nucleic acid sequence (or a portion thereof) contains or encodes an EGF-like domain of NRG1.

[0369] Abnormal cell lines containing the ZFAT-NRG1 polynucleotide fusion or expressing the polypeptide fusion contain or encode an EGF-like domain of NRG1. For detection, diagnosis, or identification purposes, it is sufficient to demonstrate that the fusion junction between ZFAT and NRG1 is within a reading frame and occurs at a location that would allow the resulting fusion product, nucleic acid, or protein to contain an EGF-like domain of NRG1. The EGF-like domain is preferably the EGF-like domain of SEQ ID NO: 163 or its counterpart variant and has at least 85% identity with SEQ ID NO: 163, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0370] A polynucleotide fusion comprising a portion of exon 12 of ZFAT and a portion of exon 6 of NRG1 is also provided. Exon 12 of ZFAT is preferably an exon of the opposite gene variant of SEQ ID NO: 841 or SEQ ID NO: 841, and exon 6 of NRG1 is preferably an exon of the opposite gene variant of SEQ ID NO: 130 or SEQ ID NO: 130.

[0371] When present in abnormal cells of a patient or individual, the polynucleotide fusion preferably further comprises any sequence at 5' of exon 12 of ZFAT and any sequence at 3' of exon 6 of NRG1, but the presence of at least SEQ ID NO: 841 and 130 may be sufficient for detection of the fusion junction using a polynucleotide-based assay. Any sequence from 5' of exon 12 of ZFAT comprises or consists of one or all of SEQ ID NO: 830-840 (or any variant of SEQ ID NO: 830-840), and any sequence from 3' of exon 6 of NRG1 comprises or consists of one or all of SEQ ID NO: 131-137 (or any variant of SEQ ID NO: 131-137).

[0372] Preferably, the ZFAT exon 12 dual gene variant has at least 85% identity with SEQ ID NO: 841, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity, and the NRG1 exon 6 dual gene variant has at least 85% identity with SEQ ID NO: 130, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity.

[0373] Preferably, the portion of exon 12 of ZFAT comprises or is based on SEQ ID NO: 826, and its dual gene variant has at least 85% identity with SEQ ID NO: 826, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. The portion of exon 6 of NRG1 in the fusion with ZFAT preferably comprises or includes the sequence as in SEQ ID NO: 827, and its dual gene variant has at least 85% identity with SEQ ID NO: 827, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, the portion of exon 12 of ZFAT comprises or is composed 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: 826, and includes 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, or 40 of SEQ ID NO: 826, or all of them, and shall include at least the nucleic acid at position 75. More preferably, the portion of exon 12 of ZFAT comprises or is based on SEQ ID NO: 826 or its dual gene variant. Such short polynucleotide sequences are particularly useful for detecting the presence of large polynucleotide fusions between ZFAT and NRG1 and for determining whether such fusions are oncogenic fusions containing an EGF-like domain of NRG1 within a reading frame.

[0374] Alternatively, a portion of ZFAT exon 12 comprises or is composed of SEQ ID NO: 841 (or a variant of SEQ ID NO: 841), including at least the nucleic acid at position 139. Preferably, a portion of ZFAT exon 12 comprises or is composed of 2 to about 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids derived from or composed of SEQ ID NO: 841 or its variants, including at least the nucleic acid at position 139. 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, or 40, or all of the nucleic acids of SEQ ID NO: 841, and shall include at least the nucleic acid at position 139. In this alternative example, the portion of ZFAT exon 12 preferably comprises or is based on SEQ ID NO: 841 or its dual gene variant. Preferably, the NRG1 exon 6 portion of the fusion with ZFAT comprises 2 to 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from SEQ ID NO: 130 or its dual gene variant, or is composed of such nucleic acids, and includes 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 or all of the nucleic acids from SEQ ID NO: 130, and includes at least the nucleic acid at position 1.

[0375] In an alternative preferred embodiment, the polynucleotide comprising a portion of ZFAT exon 12 fused to a portion of NRG1 exon 2 comprises about 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids from SEQ ID NO: 828, 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 from SEQ ID NO: 828, and at least includes the nucleic acids at positions 75 and 76. SEQ ID NO: 828 includes a junction between ZFAT and NRG1, particularly a junction located between a nucleic acid originating from position 75 of ZFAT and a nucleic acid originating from position 76 of NRG1. Preferably, the polynucleotide comprising a portion of ZFAT exon 12 and a portion of NRG1 exon 6 has the polynucleotide sequence of SEQ ID NO: 828 or a variant thereof.

[0376] Preferably, any ZFAT-NRG1 polynucleotide fusion provided herein is a fusion of ZFAT and NRG1 within a matching reading frame. More preferably, the fusion is a fusion of a matching reading frame comprising exon 12 or a portion of exon 12 of ZFAT and exon 6 or a portion of exon 6 of NRG1. The matching reading frame fusion is preferably a fusion of SEQ ID NO: 828 or its dual gene variant, and the dual gene variant has at least 85% identity with SEQ ID NO: 828, preferably at least 90%, 92%, 94%, 96%, or even 98% identity.

[0377] Preferably, a portion of ZFAT exon 12 (or its paired gene variant) is located at the 5' of NRG1 exon 6 (or its paired gene variant). This nucleotide-level alignment results in the 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, wherein the NRG1 portion also provides its EGF-like domain. The ZFAT-NRG1 fusion protein thus retains the EGF-like domain of NRG1 and its ability to drive the proliferation and survival of a small group of human cancers, particularly non-small cell lung cancer. DSCAML1-NRG1 polynucleotide fusion

[0378] According to this disclosure, a polynucleotide comprising a fusion of a DSCAML1 nucleic acid sequence (or a portion thereof) and an NRG1 nucleic acid sequence (or a portion thereof) is also provided. The fusion also includes variants of the DSCAML1 and NRG1 nucleic acid sequences.

[0379] Preferably, the DSCAML1 nucleic acid sequence (or a portion thereof) comprises, or is composed of, any of the pairs of SEQ ID NO: 870-903 or any of the pairs of SEQ ID NO: 870-903, and the NRG1 nucleic acid sequence (or a portion thereof) comprises, or is composed of, any of the pairs of SEQ ID NO: 125-138 or any of the pairs of SEQ ID NO: 125-138. More preferably, the DSCAML1 nucleic acid sequence comprises, or is composed of, a portion of the pairs of SEQ ID NO: 903 or SEQ ID NO: 903, and the NRG1 nucleic acid sequence comprises, or is composed of, a portion of the pairs of SEQ ID NO: 138 or SEQ ID NO: 138. SEQ ID NO: 870-902 correspond to exons 1-33 of DSCAML1 according to NM_020693.4. SEQ ID NO: 903 corresponds to exons 1-33 of DSCAML1 according to NM_020693.4. SEQ ID NO: 125-137 correspond to exons 1-13 of NRG1 according to NM_001159999.3. SEQ ID NO: 138 corresponds to exons 1-13 of NRG1 according to NM_001159999.3.

[0380] In a preferred embodiment, the DSCAML1 nucleic acid sequence portion comprises 2 to 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from any of SEQ ID NO: 870-903 (or the dual gene variant of any of SEQ ID NO: 870-903), while the NRG1 nucleic acid sequence portion comprises 2 to 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from any of SEQ ID NO: 125-138 (or the dual gene variant of any of SEQ ID NO: 125-138).

[0381] Preferably, the dual gene variant of the DSCAML1 nucleic acid sequence has at least 85% identity with any of SEQ ID NO: 870-903, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity; and the dual gene variant of the NRG1 nucleic acid sequence has at least 85% identity with any of SEQ ID NO: 125-138, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity.

[0382] Preferably, the DSCAML1 nucleic acid sequence or a portion thereof is located at the 5' position of the NRG1 nucleic acid sequence or a portion thereof.

[0383] Preferably, the polynucleotide comprising the fusion of the DSCAML1 nucleic acid sequence (or a portion thereof) and the NRG1 nucleic acid sequence (or a portion thereof) contains or encodes the EGF-like domain of NRG1.

[0384] Abnormal cell lines containing the DSCAML1-NRG1 polynucleotide fusion or expressing the polypeptide fusion contain or encode an EGF-like domain of NRG1. For detection, diagnosis, or identification purposes, it is sufficient to demonstrate that the fusion junction between DSCAML1 and NRG1 is within a reading frame and occurs at a location that would allow the resulting fusion product, nucleic acid, or protein to contain an EGF-like domain of NRG1. The EGF-like domain is preferably the EGF-like domain of SEQ ID NO: 163 or its counterpart variant and has at least 85% identity with SEQ ID NO: 163, more preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity.

[0385] A polynucleotide fusion comprising a portion of exon 3 of DSCAML1 and a portion of exon 2 of NRG1 is also provided. Exon 3 of DSCAML1 is preferably an exon of the opposite gene variant of SEQ ID NO: 872 or SEQ ID NO: 872, and exon 2 of NRG1 is preferably an exon of the opposite gene variant of SEQ ID NO: 126 or SEQ ID NO: 126.

[0386] When present in abnormal cells of a patient or individual, the polynucleotide fusion preferably further comprises any sequence at the 5' of exon 3 of DSCAML1 and any sequence at the 3' of exon 2 of NRG1, but the presence of at least SEQ ID NO: 872 and 126 may be sufficient for detection of the fusion junction using a polynucleotide-based assay. Any sequence from the 5' of exon 3 of DSCAML1 comprises or consists of one or all of SEQ ID NO: 870-871 (or any variant of SEQ ID NO: 870-871), and any sequence from the 3' of exon 2 of NRG1 comprises or consists of one or all of SEQ ID NO: 127-137 (or any variant of SEQ ID NO: 127-137).

[0387] Preferably, the dual gene variant of exon 3 of DSCAML1 has at least 85% identity with SEQ ID NO: 872, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity, and the dual gene variant of exon 2 of NRG1 has at least 85% identity with SEQ ID NO: 126, more preferably at least 90% identity, and 92%, 94%, 96% or more preferably at least 98% sequence identity.

[0388] Preferably, the exon 3 portion of DSCAML1 comprises or is based on SEQ ID NO: 866, and its paired gene variant has at least 85% identity with SEQ ID NO: 866, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. The exon 2 portion of NRG1 in the fusion with DSCAML1 preferably comprises or includes the sequence as in SEQ ID NO: 867, and its paired gene variant has at least 85% identity with SEQ ID NO: 867, preferably at least 90% identity, and 92%, 94%, 96%, or more preferably at least 98% sequence identity. More preferably, the exon 3 portion of DSCAML1 comprises or is composed of up to 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids from SEQ ID NO: 866, and includes 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, or 40, or all of the nucleic acids listed in SEQ ID NO: 826, and at least includes the nucleic acid at position 75. More preferably, the portion of exon 3 of DSCAML1 contains or is based on SEQ ID NO: 866 or its dual gene variant. Such short polynucleotide sequences are particularly useful for detecting the presence of large polynucleotide fusions between DSCAML1 and NRG1 and for determining whether such fusions are oncogenic fusions containing an EGF-like domain of NRG1 within a reading frame.

[0389] Alternatively, the portion of exon 3 of DSCAML1 comprises or is composed of SEQ ID NO: 872 (or a variant of SEQ ID NO: 872), including at least the nucleic acid at position 147. Preferably, the portion of exon 3 of DSCAML1 comprises or is composed of 2 to about 10, about 20, about 30, or up to about 40 or even all of the consecutive nucleic acids derived from or derived from SEQ ID NO: 872 or its variant, including at least the nucleic acid at position 147. 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, or 40, or all of the nucleic acids of SEQ ID NO: 872, and shall include at least the nucleic acid at position 147. In this alternative example, a portion of exon 3 of DSCAML1 preferably comprises or is based on SEQ ID NO: 872 or its dual gene variant. Preferably, the NRG1 exon 2 portion of the fusion with DSCAML1 comprises or consists of 2 to about 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from SEQ ID NO: 126 or its dual gene variant, and includes 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 or all of the nucleic acids from SEQ ID NO: 126, and includes at least the nucleic acid at position 1.

[0390] In an alternative preferred embodiment, the polynucleotide comprising a portion of DSCAML1 exon 3 fused to a portion of NRG1 exon 2 comprises up to 10, about 20, about 30, or up to about 40 or even all of the nucleic acids from SEQ ID NO: 868, 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 from SEQ ID NO: 868, and at least includes the nucleic acids at positions 75 and 76. SEQ ID NO: 868 includes a junction between DSCAML1 and NRG1, particularly between a nucleic acid originating from position 75 of DSCAML1 and a nucleic acid originating from position 76 of NRG1. Preferably, the polynucleotide comprising a portion of exon 3 of DSCAML1 and a portion of exon 2 of NRG1 has the polynucleotide sequence of SEQ ID NO: 868 or a variant thereof.

[0391] Preferably, any DSCAML1-NRG1 polynucleotide fusion provided herein is a fusion of a reading frame matching DSCAML1 and NRG1. More preferably, the fusion is a fusion of a reading frame matching DSCAML1 containing exon 3 or a portion of exon 3 and NRG1 containing exon 2 or a portion of exon 2. The fusion of the reading frame matching is preferably a fusion of SEQ ID NO: 868 or its dual gene variant, and the dual gene variant has at least 85% identity with SEQ ID NO: 868, preferably at least 90%, 92%, 94%, 96% or even 98% identity.

[0392] Preferably, a portion of exon 3 of DSCAML1 (or a variant thereof) is located at the 5' position of exon 2 of NRG1 (or a variant thereof). This nucleotide alignment results in the fusion polypeptide product containing the N-terminus of DSCAML1 and the C-terminus of NRG1. Furthermore, the DSCAML1-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 DSCAML1, and the portion from the junction to the C-terminus is a polypeptide sequence from NRG1, wherein the NRG1 portion also provides its EGF-like domain. The DSCAML1-NRG1 fusion protein thus retains the EGF-like domain of NRG1 and its ability to drive the proliferation and survival of a small group of human cancers, particularly adenocarcinoma, and more particularly pancreatic ductal adenocarcinoma.

[0393] Each polynucleotide fusion containing NRG1 mentioned herein, 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 includes the isolation of one or more polynucleotide-containing components from a sample. This one or more components containing polynucleotides are typically isolated from any cell or cellular material in the sample. NRG1 polypeptide fusion.

[0394] According to this disclosure, peptide fusions containing NRG1 are now 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, ASPH-NRG1, NOTCH2-NRG1, CD74-NRG1, SDC4-NRG1, SLC4A4-NRG1, ZFAT-NRG1, and DSCAML1-NRG1. In particular, such fusions are present or have been identified in human patients diagnosed with cancer, and are described in more detail in the following section. VAPB-NRG1 peptide fusion

[0395] According to this disclosure, a polypeptide fusion product encoded by a polynucleotide comprising a VAPB nucleic acid sequence (or a portion thereof) and an NRG1 nucleic acid sequence (or a portion thereof) is also provided. The VAPB nucleic acid sequence (or a portion thereof) preferably encodes a sequence comprising or composed of any of SEQ ID NO: 24-30 (or a variant of the opposite gene of any of SEQ ID NO). The NRG1 nucleic acid sequence (or a portion thereof) preferably encodes a sequence comprising or composed of any of SEQ ID NO: 139-152 (or a variant of the opposite gene of any of SEQ ID NO).

[0396] The VAPB dual gene variant of any one of SEQ ID NO: 24-30 preferably has at least 85% sequence identity with the sequences thereon, more preferably 90%, 92%, 94%, 96% or even more preferably at least 98% sequence identity. The NRG1 dual gene variant of any one of SEQ ID NO...

Claims

1. A polynucleotide comprising: - a PVALB nucleic acid sequence or a variant thereof fused with an NRG1 nucleic acid sequence or a variant thereof; or - an ASPH nucleic acid sequence or a variant thereof fused with an NRG1 nucleic acid sequence or a variant thereof; or - a DAAM1 nucleic acid sequence or a variant thereof fused with an NRG1 nucleic acid sequence or a variant thereof; or - a ZFAT nucleic acid sequence or a variant thereof fused with an NRG1 nucleic acid sequence or a variant thereof; or - a DSCAML1 nucleic acid sequence or a variant thereof fused with an NRG1 nucleic acid sequence or a variant thereof.

2. The polynucleotide of claim 1, wherein: - the PVALB nucleic acid sequence comprises or consists of any one of SEQ ID NO: 439-444, or comprises or consists of a variant of the opposite gene of any one of SEQ ID NO: 439-444, and the NRG1 nucleic acid sequence comprises or consists of any one of SEQ ID NO: 125-138; - the DAAM1 nucleic acid sequence comprises or consists of any one of SEQ ID NO: 606-631, or comprises or consists of a variant of the opposite gene of any one of SEQ ID NO: 606-631, and the NRG1 nucleic acid sequence comprises or consists of any one of SEQ ID NO: 125-138; - the ZFAT nucleic acid sequence comprises or consists of any one of SEQ ID NO: 830-846, or comprises or consists of a variant of the opposite gene of any one of SEQ ID NO: 830-846. The NRG1 nucleic acid sequence comprises or consists of a variant of the pair of any of SEQ ID NO: 125-138; or the DSCAML1 nucleic acid sequence comprises or consists of any of SEQ ID NO: 870-903, or comprises or consists of a variant of the pair of any of SEQ ID NO: 870-903, and the NRG1 nucleic acid sequence comprises or consists of any of SEQ ID NO: 125-138.

3. The polynucleotide of claim 1, wherein the PVALB, DAAM1, ZFAT or DSCAML1 nucleic acid sequence or its dual gene variant system is located at the 5' end of the NRG1 nucleic acid sequence or its dual gene variant.

4. The polynucleotide of claim 1, wherein - the paired gene variant of the PVALB nucleic acid sequence shares at least 85% identity with any of SEQ ID NO: 439-444; and the paired gene variant of the NRG1 nucleic acid sequence shares at least 85% identity with any of SEQ ID NO: 125-138; - the paired gene variant of the DAAM1 nucleic acid sequence shares at least 85% identity with any of SEQ ID NO: 606-631; and the paired gene variant of the NRG1 nucleic acid sequence shares at least 85% identity with any of SEQ ID NO: 125-138; - the paired gene variant of the ZFAT nucleic acid sequence shares at least 85% identity with any of SEQ ID NO: 830-846; and the paired gene variant of the NRG1 nucleic acid sequence shares at least 85% identity with any of SEQ ID NO: 125-138; or - The dual gene variant of the DSCAML1 nucleic acid sequence has at least 85% identity with any of SEQ ID NO: 870-903; and the dual gene variant of the NRG1 nucleic acid sequence has at least 85% identity with any of SEQ ID NO: 125-138.

5. The polynucleotide of claim 1, wherein - the fusion of the PVALB nucleic acid and the NRG1 nucleic acid comprises SEQ ID NO: 437; - the fusion of the DAAM1 nucleic acid and the NRG1 nucleic acid comprises SEQ ID NO: 605; - the fusion of the ZFAT nucleic acid and the NRG1 nucleic acid comprises SEQ ID NO: 828; or - the fusion of the DSCAML1 nucleic acid and the NRG1 nucleic acid comprises SEQ ID NO:

868.

6. The polynucleotide of claim 1, wherein the nucleic acid encoding the NRG1 protein sequence or its dual gene variant system contains or encodes an EGF-like domain of NRG1.

7. The polynucleotide of claim 6, wherein the EGF-like domain is the EGF-like domain of SEQ ID NO:

163.

8. A polynucleotide comprising: - a portion of exon 1 or a variant of exon 1 of VAPB, fused with a portion of exon 2 or a variant of exon 2 of NRG1, wherein the portion of exon 1 of VAPB is or contains SEQ ID NO: 1 or a variant of exon 1 thereof and the portion of exon 2 of NRG1 is or contains SEQ ID NO: 165 or a variant of exon 2 thereof; - a portion of exon 7 or a variant of exon 7 of CADM1, fused with a portion of exon 6 or a variant of exon 6 of NRG1, wherein the portion of exon 7 of CADM1 is or contains SEQ ID NO: 5 or a variant of exon 5 thereof and the portion of exon 6 of NRG1 is or contains SEQ ID NO: 6 or a variant of exon 6 thereof; - A portion of exon 5 or its paired variant of CD44, and a portion of exon 2 or its paired variant of NRG1, wherein the portion of exon 5 of CD44 is or contains SEQ ID NO: 9 or its paired variant, and the portion of exon 2 of NRG1 is or contains SEQ ID NO: 165 or its paired variant; - A portion of exon 1 or its paired variant of transcript 6 of SLC3A2, and a portion of exon 5 or its paired variant of NRG1, wherein the portion of exon 1 of SLC3A2 is or contains SEQ ID NO: 13 or its paired variant, and the portion of exon 5 of NRG1 is or contains SEQ ID NO: 14 or its paired variant; - - A portion of exon 2 or its dual gene variant of VTCN1, and a portion of exon 2 or its dual gene variant of NRG1, wherein the portion of exon 2 of VTCN1 is or contains SEQ ID NO: 164 or its dual gene variant and the portion of exon 2 of NRG1 is or contains SEQ ID NO: 165 or its dual gene variant; - A portion of exon 11 or its dual gene variant of CDH1, and a portion of exon 2 or its dual gene variant of NRG1, wherein the portion of exon 11 of CDH1 is or contains SEQ ID NO: 184 or its dual gene variant and the portion of exon 2 of NRG1 is or contains SEQ ID NO: 165 or its dual gene variant;- A portion of exon 1 or its paired gene variant of CXADR, and a portion of exon 2 or its paired gene variant of NRG1, wherein the portion of exon 1 of CXADR is or contains SEQ ID NO: 215 or its paired gene variant and the portion of exon 2 of NRG1 is or contains SEQ ID NO: 165 or its paired gene variant; - A portion of exon 2 or its paired gene variant of GTF2E2, and a portion of exon 2 or its paired gene variant of NRG1, wherein the portion of exon 2 of GTF2E2 is or contains SEQ ID NO: 231 or its paired gene variant and the portion of exon 2 of NRG1 is or contains SEQ ID NO: 165 or its paired gene variant; - A portion of exon 23 or its paired variant of CSMD1, and a portion of exon 6 or its paired variant of NRG1, wherein the portion of exon 23 of CSMD1 is or contains SEQ ID NO: 253 or its paired variant, and the portion of exon 6 of NRG1 is or contains SEQ ID NO: 6 or its paired variant; - A portion of exon 4 or its paired variant of PTN, and a portion of exon 2 or its paired variant of NRG1, wherein the portion of exon 4 of PTN is or contains SEQ ID NO: 311 or its paired variant, and the portion of exon 2 of NRG1 is or contains SEQ ID NO: 165 or its paired variant; - A portion of exon 11 or its dual gene variant of ST14, and a portion of exon 6 or its dual gene variant of NRG1, wherein the portion of exon 11 of ST14 is or contains SEQ ID NO: 328 or its dual gene variant and the portion of exon 6 of NRG1 is or contains SEQ ID NO: 6 or its dual gene variant; - a portion of exon 9 or its dual gene variant of THBS1, and a portion of exon 6 or its dual gene variant of NRG1, wherein the portion of exon 9 of THBS1 is or contains SEQ ID NO: 374 or its dual gene variant and the portion of exon 6 of NRG1 is or contains SEQ ID NO: 6 or its dual gene variant;- A portion of exon 12 or its paired variant of AGRN, and a portion of exon 6 or its paired variant of NRG1, wherein the portion of exon 12 of AGRN is or contains SEQ ID NO: 401 or its paired variant and the portion of exon 6 of NRG1 is or contains SEQ ID NO: 6 or its paired variant; - A portion of exon 4 or its paired variant of PVALB, and a portion of exon 6 or its paired variant of NRG1, wherein the portion of exon 4 of PVALB is or contains SEQ ID NO: 435 or its paired variant and the portion of exon 6 of NRG1 is or contains SEQ ID NO: 6 or its paired variant; - - A portion of exon 2 or its paired variant of transcript 3 of SLC3A2, and a portion of exon 6 or its paired variant of NRG1, wherein the portion of exon 2 of SLC3A2 is or contains SEQ ID NO: 452 or its paired variant and the portion of exon 6 of NRG1 is or contains SEQ ID NO: 6 or its paired variant; - A portion of exon 14 or its paired variant of APP, and a portion of exon 6 or its paired variant of NRG1, wherein the portion of exon 14 of APP is or contains SEQ ID NO: 484 or its paired variant and the portion of exon 6 of NRG1 is or contains SEQ ID NO: 6 or its paired variant; - A portion of exon 33 of WRN or a variant of its opposite gene, and a portion of exon 6 of NRG1 or a variant of its opposite gene, wherein the portion of exon 33 of WRN is or contains SEQ ID NO: 526 or its opposite gene variant and the portion of exon 6 of NRG1 is or contains SEQ ID NO: 6 or its opposite gene variant; - A portion of exon 1 of DAAM1 or a variant of its opposite gene, and a portion of exon 1 of NRG1 or a variant of its opposite gene, wherein the portion of exon 1 of DAAM1 is or contains SEQ ID NO: 603 or its opposite gene variant and the portion of exon 1 of NRG1 is or contains SEQ ID NO: 604 or its opposite gene variant;- A portion of exon 22 or its paired variant of ASPH, and a portion of exon 2 or its paired variant of NRG1, wherein the portion of exon 22 of ASPH is or contains SEQ ID NO: 633 or its paired variant, and the portion of exon 2 of NRG1 is or contains SEQ ID NO: 165 or its paired variant; - A portion of exon 6 or its paired variant of NOTCH2, and a portion of exon 6 or its paired variant of NRG1, wherein the portion of exon 6 of NOTCH2 is or contains SEQ ID NO: 691 or its paired variant, and the portion of exon 6 of NRG1 is or contains SEQ ID NO: 6 or its paired variant; - A portion of exon 2 or its dual variant of CD74, and a portion of exon 2 or its dual variant of NRG1, wherein the portion of exon 2 of CD74 is or contains SEQ ID NO: 715 or its dual variant and the portion of exon 2 of NRG1 is or contains SEQ ID NO: 165 or its dual variant; - A portion of exon 2 or its dual variant of SDC4, and a portion of exon 2 or its dual variant of NRG1, wherein the portion of exon 2 of SDC4 is or contains SEQ ID NO: 741 or its dual variant and the portion of exon 2 of NRG1 is or contains SEQ ID NO: 165 or its dual variant; - A portion of exon 5 or its dual gene variant of CD44, and a portion of exon 6 or its dual gene variant of NRG1, wherein the portion of exon 5 of CD44 is or contains SEQ ID NO: 759 or its dual gene variant and the portion of exon 6 of NRG1 is or contains SEQ ID NO: 6 or its dual gene variant; - A portion of exon 14 or its dual gene variant of SLC4A4, and a portion of exon 6 or its dual gene variant of NRG1, wherein the portion of exon 14 of SLC4A4 is or contains SEQ ID NO: 763 or its dual gene variant and the portion of exon 6 of NRG1 is or contains SEQ ID NO: 6 or its dual gene variant;- A portion of exon 4 or its dual variant of SDC4, and a portion of exon 2 or its dual variant of NRG1, wherein the portion of exon 4 of SDC4 is or contains SEQ ID NO: 822 or its dual variant and the portion of exon 2 of NRG1 is or contains SEQ ID NO: 165 or its dual variant; - A portion of exon 12 or its dual variant of ZFAT, and a portion of exon 6 or its dual variant of NRG1, wherein the portion of exon 12 of ZFAT is or contains SEQ ID NO: 826 or its dual variant and the portion of exon 6 of NRG1 is or contains SEQ ID NO: 6 or its dual variant; or - A portion of exon 3 or its dual variant of DSCAML1, and a portion of exon 2 or its dual variant of NRG1, wherein the portion of exon 3 of DSCAML1 is or contains SEQ ID NO: 866 or its dual variant, and the portion of exon 2 of NRG1 is or contains SEQ ID NO: 165 or its dual variant.

9. The polynucleotide of claim 8, wherein exon 1 of VAPB is exon SEQ ID NO: 17; exon 7 of CADM1 is exon SEQ ID NO: 39; exon 5 of CD44 is exon SEQ ID NO: 65; exon 1 of SLC3A2 is exon SEQ ID NO: 103; exon 2 of VTCN1 is exon SEQ ID NO: 169; exon 11 of CDH1 is exon SEQ ID NO: 198; exon 1 of CXADR is exon SEQ ID NO: 219; exon 2 of GTF2E2 is exon SEQ ID NO: 236; exon 23 of CSMD1 is exon SEQ ID NO: 279; exon 4 of PTN is exon SEQ ID NO: 318; exon 11 of ST14 is exon SEQ ID NO: 342; and exon 9 of THBS1 is exon SEQ ID NO:

342. Exon 386; AGRN exon 12 is SEQ ID NO: 416; PVALB exon 4 is SEQ ID NO: 442; SLC3A2 exon 2 is SEQ ID NO: 457; APP exon 14 is SEQ ID NO: 501; WRN exon 33 is SEQ ID NO: 562; DAAM1 exon 1 is SEQ ID NO: 606; ASPH exon 22 is SEQ ID NO: 658; NOTCH2 exon 6 is SEQ ID NO: 700; CD74 exon 2 is SEQ ID NO: 720; SDC4 exon 2 is SEQ ID NO: 746; CD44 exon 5 is SEQ ID NO: 65; SLC4A4 exon 14 is SEQ ID NO: Exon 780; Exon 4 of SDC4 is exon SEQ ID NO: 748; Exon 12 of ZFAT is exon SEQ ID NO: 841; Exon 3 of DSCAML1 is exon SEQ ID NO: 872, and exons 1, 2, 5 and 6 of NRG1 are exons SEQ ID NO: 125, 126, 129 and 130 respectively.

10. The polynucleotides as described in claim 8, wherein: - The variant portion of exon 1 of VAPB or its paired gene is located at the 5' end of the variant portion of exon 2 of NRG1 or its paired gene; - The variant portion of exon 7 of CADM1 or its paired gene is located at the 5' end of the variant portion of exon 6 of NRG1 or its paired gene; - The variant portion of exon 5 of CD44 or its paired gene is located at the 5' end of the variant portion of exon 2 of NRG1 or its paired gene; - The variant portion of exon 1 of SLC3A2 or its paired gene is located at the 5' end of the variant portion of exon 5 of NRG1 or its paired gene; - The variant portion of exon 2 of VTCN1 or its paired gene is located at the 5' end of the variant portion of exon 2 of NRG1 or its paired gene; - The variant portion of exon 11 of CDH1 or its paired gene is located at the 5' end of the variant portion of exon 2 of NRG1 or its paired gene; The exon 1 of CXADR or its dual gene variant is located at the 5' end of the exon 2 of NRG1 or its dual gene variant; - The exon 2 of GTF2E2 or its dual gene variant is located at the 5' end of the exon 2 of NRG1 or its dual gene variant; - The exon 23 of CSMD1 or its dual gene variant is located at the 5' end of the exon 6 of NRG1 or its dual gene variant; - The exon 4 of PTN or its dual gene variant is located at the 5' end of the exon 2 of NRG1 or its dual gene variant; - The exon 11 of ST14 or its dual gene variant is located at the 5' end of the exon 6 of NRG1 or its dual gene variant; - The exon 9 of THBS1 or its dual gene variant is located at the 5' end of the exon 6 of NRG1 or its dual gene variant; The AGRN exon 12 or its dual gene variant portion is located at the 5' end of the NRG1 exon 6 or its dual gene variant portion; - The PVALB exon 4 or its dual gene variant portion is located at the 5' end of the NRG1 exon 6 or its dual gene variant portion; - The SCL3A2 exon 2 or its dual gene variant portion is located at the 5' end of the NRG1 exon 6 or its dual gene variant portion; - The APP exon 14 or its dual gene variant portion is located at the 5' end of the NRG1 exon 6 or its dual gene variant portion; - The WRN exon 33 or its dual gene variant portion is located at the 5' end of the NRG1 exon 6 or its dual gene variant portion; - The DAAM1 exon 1 or its dual gene variant portion is located at the 5' end of the NRG1 exon 1 or its dual gene variant portion.- The ASPH exon 22 or its dual gene variant portion is located at the 5' end of exon 2 or the dual gene variant portion of exon 2 of NRG1; - The NOTCH2 exon 6 or its dual gene variant portion is located at the 5' end of exon 6 or the dual gene variant portion of exon 6 of NRG1; - The CD74 exon 2 or its dual gene variant portion is located at the 5' end of exon 2 or the dual gene variant portion of exon 2 of NRG1; - The SDC4 exon 2 or its dual gene variant portion is located at the 5' end of exon 2 or the dual gene variant portion of exon 2 of NRG1; - The CD44 exon 5 or its dual gene variant portion is located at the 5' end of exon 6 or the dual gene variant portion of exon 6 of NRG1; The exon 14 of SLC4A4 or its dual gene variant is located at the 5' end of exon 6 of NRG1 or its dual gene variant; - the exon 4 of SDC4 or its dual gene variant is located at the 5' end of exon 2 of NRG1 or its dual gene variant; - the exon 12 of ZFAT or its dual gene variant is located at the 5' end of exon 6 of NRG1 or its dual gene variant; and - the exon 3 of DSCAML1 or its dual gene variant is located at the 5' end of exon 2 of NRG1 or its dual gene variant.

11. The polynucleotides as described in claim 8, wherein: - The paired gene variant of the VAPB exon 1 nucleotide sequence shows at least 94% identity with SEQ ID NO: 1; - The paired gene variant of the CADM1 exon 7 nucleotide sequence shows at least 94% identity with SEQ ID NO: 5; - The paired gene variant of the CD44 exon 5 nucleotide sequence shows at least 94% identity with SEQ ID NO: 9; - The paired gene variant of the SLC3A2 transcript 6 exon 1 nucleotide sequence shows at least 94% identity with SEQ ID NO: 13; - The paired gene variant of the VTCN1 exon 2 nucleotide sequence shows at least 94% identity with SEQ ID NO: 164; - The paired gene variant of the CDH1 exon 11 nucleotide sequence shows at least 94% identity with SEQ ID NO: 184; - The paired gene variant of the NRG1 exon 2 nucleotide sequence shows at least 94% identity with SEQ ID NO: 165; The paired gene variant of exon 5 of NRG1 shows at least 94% identity with SEQ ID NO: 14; - The paired gene variant of exon 6 of NRG1 shows at least 94% identity with SEQ ID NO: 6; - The paired gene variant of exon 1 of NRG1 shows at least 94% identity with SEQ ID NO: 604; - The paired gene variant of exon 1 of CXADR shows at least 94% identity with SEQ ID NO: 215; - The paired gene variant of exon 2 of GTF2E2 shows at least 94% identity with SEQ ID NO: 231; - The paired gene variant of exon 23 of CSMD1 shows at least 94% identity with SEQ ID NO: 253; - The paired gene variant of exon 4 of PTN shows at least 94% identity with SEQ ID NO: 311; The paired gene variant of exon 11 of ST14 showed at least 94% identity with SEQ ID NO: 328; the paired gene variant of exon 9 of THBS1 showed at least 94% identity with SEQ ID NO: 374; the paired gene variant of exon 12 of AGRN showed at least 94% identity with SEQ ID NO: 401; the paired gene variant of exon 4 of PVALB showed at least 94% identity with SEQ ID NO: 435; the paired gene variant of exon 2 of transcript 3 of SLC3A2 showed at least 94% identity with SEQ ID NO: 452; and the paired gene variant of exon 14 of APP showed at least 94% identity with SEQ ID NO: 484.- The paired gene variant of the WRN exon 33 sequence shows at least 94% identity with SEQ ID NO: 526; - The paired gene variant of the DAAM1 exon 1 sequence shows at least 94% identity with SEQ ID NO: 603; - The paired gene variant of the ASPH exon 22 sequence shows at least 94% identity with SEQ ID NO: 633; ​​- The paired gene variant of the NOTCH2 exon 6 sequence shows at least 94% identity with SEQ ID NO: 691; - The paired gene variant of the CD74 exon 2 sequence shows at least 94% identity with SEQ ID NO: 715; - The paired gene variant of the SDC4 exon 2 sequence shows at least 94% identity with SEQ ID NO: 741; - The paired gene variant of the CD44 exon 5 sequence shows at least 94% identity with SEQ ID NO: 759; The dual gene variant of exon 14 of SLC4A4 shows at least 94% identity with SEQ ID NO: 763; the dual gene variant of exon 4 of SDC4 shows at least 94% identity with SEQ ID NO: 822; the dual gene variant of exon 12 of ZFAT shows at least 94% identity with SEQ ID NO: 826; and the dual gene variant of exon 3 of DSCAML1 shows at least 94% identity with SEQ ID NO:

866.

12. The polynucleotides as described in claim 8, wherein: - The VAPB / NRG1 fusion contains SEQ ID NO: 3 or its dual gene variant; - The CADM1 / NRG1 fusion contains SEQ ID NO: 7 or its dual gene variant; - The CD44 / NRG1 fusion contains SEQ ID NO: 11 or its dual gene variant; - The SLC3A2 / NRG1 fusion contains SEQ ID NO: 15 or its dual gene variant; - The VTCN1 / NRG1 fusion contains SEQ ID NO: 166 or its dual gene variant; - The CDH1 / NRG1 fusion contains SEQ ID NO: 186 or its dual gene variant; - The CXADR / NRG1 fusion contains SEQ ID NO: 217 or its dual gene variant; - The GTF2E2 / NRG1 fusion contains SEQ ID NO: 233 or its dual gene variant; - The CSMD1 / NRG1 fusion contains SEQ ID NO: - The fusion of PTN and NRG1 contains SEQ ID NO: 313 or its dual gene variant; - The fusion of ST14 and NRG1 contains SEQ ID NO: 330 or its dual gene variant; - The fusion of THBS1 and NRG1 contains SEQ ID NO: 376 or its dual gene variant; - The fusion of AGRN and NRG1 contains SEQ ID NO: 403 or its dual gene variant; - The fusion of PVALB and NRG1 contains SEQ ID NO: 437 or its dual gene variant; - The fusion of SLC3A2 and NRG1 contains SEQ ID NO: 454 or its dual gene variant; - The fusion of APP and NRG1 contains SEQ ID NO: 486 or its dual gene variant; - The fusion of WRN and NRG1 contains SEQ ID NO: 528 or its dual gene variant; - The fusion of DAAM1 and NRG1 contains SEQ ID NO: 528 or its dual gene variant; - The ASPH-NRG1 fusion contains SEQ ID NO: 605 or its dual gene variant; - The NOTCH2-NRG1 fusion contains SEQ ID NO: 693 or its dual gene variant; - The CD74-NRG1 fusion contains SEQ ID NO: 717 or its dual gene variant; - The SDC4-NRG1 fusion contains SEQ ID NO: 743 or its dual gene variant; - The CD44-NRG1 fusion contains SEQ ID NO: 761 or its dual gene variant;- The SLC4A4 / NRG1 fusion contains SEQ ID NO: 765 or its dual gene variant; - The SDC4 / NRG1 fusion contains SEQ ID NO: 824 or its dual gene variant; - The ZFAT / NRG1 fusion contains SEQ ID NO: 828 or its dual gene variant; and - The DSCAML1 / NRG1 fusion contains SEQ ID NO: 868 or its dual gene variant.

13. The polynucleotides as described in claim 8, wherein: - Exon 1 of the VAPB is or contains a variant of the paired gene of SEQ ID NO: 1 or SEQ ID NO: 1; - Exon 7 of the CADM1 is or contains a variant of the paired gene of SEQ ID NO: 5 or SEQ ID NO: 5; - Exon 5 of the CD44 is or contains a variant of the paired gene of SEQ ID NO: 9 or SEQ ID NO: 9; - Exon 1 of the SLC3A2 is or contains a variant of the paired gene of SEQ ID NO: 13 or SEQ ID NO: 13; - Exon 2 of the VTCN1 is or contains a variant of the paired gene of SEQ ID NO: 164 or SEQ ID NO: 164; - Exon 11 of the CDH1 is or contains a variant of the paired gene of SEQ ID NO: 184 or SEQ ID NO: 184; - Exon 1 of the CXADR is or contains a variant of SEQ ID NO: 215 or SEQ ID NO:

215. The following are possible pairwise variants: - Exon 2 of GTF2E2 is or contains a pairwise variant of SEQ ID NO: 231 or SEQ ID NO: 231; - Exon 23 of CSMD1 is or contains a pairwise variant of SEQ ID NO: 253 or SEQ ID NO: 253; - Exon 4 of PTN is or contains a pairwise variant of SEQ ID NO: 311 or SEQ ID NO: 311; - Exon 11 of ST14 is or contains a pairwise variant of SEQ ID NO: 328 or SEQ ID NO: 328; - Exon 9 of THBS1 is or contains a pairwise variant of SEQ ID NO: 374 or SEQ ID NO: 374; - Exon 12 of AGRN is or contains a pairwise variant of SEQ ID NO: 401 or SEQ ID NO: 401; The exon 4 portion of the PVALB is or contains a variant of the paired gene of SEQ ID NO: 435 or SEQ ID NO: 435; - The exon 2 portion of the SLC3A2 is or contains a variant of the paired gene of SEQ ID NO: 452 or SEQ ID NO: 452; - The exon 2 portion of the NRG1 is or contains a variant of the paired gene of SEQ ID NO: 165 or SEQ ID NO: 165; - The exon 5 portion of the NRG1 is or contains a variant of the paired gene of SEQ ID NO: 14 or SEQ ID NO: 14;- Exon 6 of NRG1 contains or includes SEQ ID NO: 6 or its dual gene variant; - Exon 14 of APP contains or includes SEQ ID NO: 484 or its dual gene variant; - Exon 33 of WRN contains or includes SEQ ID NO: 526 or its dual gene variant; - Exon 1 of DAAM1 contains or includes SEQ ID NO: 603 or its dual gene variant; - Exon 22 of ASPH contains or includes SEQ ID NO: 633 or its dual gene variant; - Exon 6 of NOTCH2 contains or includes SEQ ID NO: 691 or its dual gene variant; - Exon 2 of CD74 contains or includes SEQ ID NO: 715 or its dual gene variant; - Exon 2 of SDC4 contains or includes SEQ ID NO: 741 or its dual gene variant; - Exon 5 of CD44 contains or includes SEQ ID NO: - SEQ ID NO: 759 or its dual gene variant; - Exon 14 of SLC4A4 is or contains SEQ ID NO: 763 or its dual gene variant; - Exon 4 of SDC4 is or contains SEQ ID NO: 822 or its dual gene variant; - Exon 12 of ZFAT is or contains SEQ ID NO: 826 or its dual gene variant; - Exon 3 of DSCAML1 is or contains SEQ ID NO: 866 or its dual gene variant; and - Exon 1 of NRG1 is or contains SEQ ID NO: 604 or its dual gene variant.

14. The polynucleotides as described in claim 8, wherein: - The fusion of VAPB and NRG1 includes a fusion junction between exon 1 of VAPB and exon 2 of NRG1; - The fusion of CADM1 and NRG1 includes a fusion junction between exon 7 of CADM1 and exon 6 of NRG1; - The fusion of CD44 and NRG1 includes a fusion junction between exon 5 of CD44 and exon 2 of NRG1; - The fusion of SLC3A2 and NRG1 includes a fusion junction between exon 1 of SLC3A2 and exon 5 of NRG1; - The fusion of VTCN1 and NRG1 includes a fusion junction between exon 2 of VTCN1 and exon 2 of NRG1; - The fusion of CDH1 and NRG1 includes a fusion junction between exon 11 of CDH1 and exon 2 of NRG1; - The fusion of CXADR and NRG1 includes a fusion junction between exon 1 of CXADR and exon 2 of NRG1; The fusion of GTF2E2 and NRG1 includes a fusion junction between exon 2 of GTF2E2 and exon 2 of NRG1; - The fusion of CSMD1 and NRG1 includes a fusion junction between exon 23 of CSMD1 and exon 6 of NRG1; - The fusion of PTN and NRG1 includes a fusion junction between exon 4 of PTN and exon 2 of NRG1; - The fusion of ST14 and NRG1 includes a fusion junction between exon 11 of ST14 and exon 6 of NRG1; - The fusion of THBS1 and NRG1 includes a fusion junction between exon 9 of THBS1 and exon 6 of NRG1; - The fusion of AGRN and NRG1 includes a fusion junction between exon 12 of AGRN and exon 6 of NRG1; - The fusion of PVALB and NRG1 includes a fusion junction between exon 4 of PVALB and exon 6 of NRG1; The fusion of SLC3A2 and NRG1 includes a fusion junction between exon 2 of SLC3A2 and exon 6 of NRG1; - The fusion of APP and NRG1 includes a fusion junction between exon 14 of APP and exon 6 of NRG1; - The fusion of WRN and NRG1 includes a fusion junction between exon 33 of WRN and exon 6 of NRG1; - The fusion of DAAM1 and NRG1 includes a fusion junction between exon 1 of DAAM1 and exon 1 of NRG1; - The fusion of ASPH and NRG1 includes a fusion junction between exon 22 of ASPH and exon 2 of NRG1; - The fusion of NOTCH2 and NRG1 includes a fusion junction between exon 6 of NOTCH2 and exon 6 of NRG1.- The fusion of CD74 and NRG1 includes a fusion junction between exon 2 of CD74 and exon 2 of NRG1; - The fusion of SDC4 and NRG1 includes a fusion junction between exon 2 of SDC4 and exon 2 of NRG1; - The fusion of CD44 and NRG1 includes a fusion junction between exon 5 of CD44 and exon 6 of NRG1; - The fusion of SLC4A4 and NRG1 includes a fusion junction between exon 14 of SLC4A4 and exon 6 of NRG1; - The fusion of SDC4 and NRG1 includes a fusion junction between exon 4 of SDC4 and exon 2 of NRG1; - The fusion of ZFAT and NRG1 includes a fusion junction between exon 12 of ZFAT and exon 6 of NRG1; and - The fusion of DSCAML1 and NRG1 includes a fusion junction between exon 3 of DSCAML1 and exon 2 of NRG1.

15. The polynucleotide as described in claim 14, wherein: - The fusion of VAPB and NRG1 includes the junction between the nucleic acid of VAPB at position 43 of SEQ ID NO: 3 and the nucleic acid of NRG1 at position 44; - The fusion of CADM1 and NRG1 includes the junction between the nucleic acid of CADM1 at position 53 of SEQ ID NO: 7 and the nucleic acid of NRG1 at position 54; - The fusion of CD44 and NRG1 includes the junction between the nucleic acid of CD44 at position 52 of SEQ ID NO: 11 and the nucleic acid of NRG1 at position 53; - The fusion of SLC3A2 and NRG1 includes the junction between the nucleic acid of SLC3A2 at position 53 of SEQ ID NO: 15 and the nucleic acid of NRG1 at position 54; - The fusion of VTCN1 and NRG1 includes the junction between the nucleic acid of VTCN1 at position 65 of SEQ ID NO: 166 and the nucleic acid of NRG1 at position 66; - The fusion of CDH1 and NRG1 includes the junction between the nucleic acid of VTCN1 at position 65 of SEQ ID NO: 166 and the nucleic acid of NRG1 at position 66; - The fusion of CDH1 at position 119 and NRG1 at position 120 contains the following: - The fusion of CXADR and NRG1 contains the following: - The fusion of CXADR at position 43 and NRG1 at position 44 contains the following: - The fusion of GTF2E2 and NRG1 contains the following: - The fusion of GTF2E2 at position 141 and NRG1 at position 142 contains the following: - The fusion of CSMD1 and NRG1 contains the following: - The fusion of CSMD1 at position 88 and NRG1 at position 89 contains the following: - The fusion of PTN and NRG1 contains the following: - The fusion of ST14 and NRG1 contains the following: - The fusion of ST14 at position 95 of SEQ ID NO: 330 and NRG1 at position 96 is a junction; - The fusion of THBS1 and NRG1 includes the fusion of THBS1 at position 56 of SEQ ID NO: 376 and NRG1 at position 57; - The fusion of AGRN and NRG1 includes the fusion of AGRN at position 106 of SEQ ID NO: 403 and NRG1 at position 107; - The fusion of PVALB and NRG1 includes the fusion of PVALB at position 102 of SEQ ID NO: 437 and NRG1 at position 103; - The fusion of SLC3A2 and NRG1 includes the fusion of SLC3A2 at position 93 of SEQ ID NO: 454 and NRG1 at position 94.- The fusion of APP and NRG1 includes a junction between the nucleotide at position 54 of APP (SEQ ID NO: 486) and the nucleotide at position 55 of NRG1; - The fusion of WRN and NRG1 includes a junction between the nucleotide at position 96 of WRN (SEQ ID NO: 528) and the nucleotide at position 97 of NRG1; - The fusion of DAAM1 and NRG1 includes a junction between the nucleotide at position 75 of DAAM1 (SEQ ID NO: 605) and the nucleotide at position 76 of NRG1; - The fusion of ASPH and NRG1 includes a junction between the nucleotide at position 75 of ASPH (SEQ ID NO: 635) and the nucleotide at position 76 of NRG1; - The fusion of NOTCH2 and NRG1 includes a junction between the nucleotide at position 75 of NOTCH2 (SEQ ID NO: 693) and the nucleotide at position 76 of NRG1; - The fusion of CD74 and NRG1 includes a junction between the nucleotide at position 75 of CD74 and the nucleotide at position 76 of NRG1; - The fusion of CD74 at position 75 and NRG1 at position 76 of SEQ ID NO: 717; - The fusion of SDC4 and NRG1 includes the junction of SDC4 at position 75 and NRG1 at position 76 of SEQ ID NO: 743; - The fusion of CD44 and NRG1 includes the junction of CD44 at position 75 and NRG1 at position 76 of SEQ ID NO: 761; - The fusion of SLC4A4 and NRG1 includes the junction of SLC4A4 at position 75 and NRG1 at position 76 of SEQ ID NO: 765; - The fusion of SDC4 and NRG1 includes the junction of SDC4 at position 75 and NRG1 at position 76 of SEQ ID NO: 824; - The fusion of ZFAT and NRG1 includes the junction of SDC4 at position 75 and NRG1 at position 76 of SEQ ID NO: 824; The junction of ZFAT at position 75 of SEQ ID NO: 828 and NRG1 at position 76; and the fusion of DSCAML1 and NRG1 includes the junction of DSCAML1 at position 75 of SEQ ID NO: 868 and NRG1 at position 76.

16. The polynucleotide of claim 1, wherein the polynucleotide is isolated or purified.

17. The polynucleotide of claim 1, wherein any of the fusions is a reading frame fusion.

18. The polynucleotide of claim 1, wherein the polynucleotide is a mammalian polynucleotide.

19. A polypeptide fusion encoded by a polynucleotide of any one of claims 1 to 18.

20. A vector comprising a polynucleotide as claimed in any one of claims 1 to 18.

21. A recombinant host cell comprising a polynucleotide as claimed in any one of claims 1 to 18.

22. A detection assay comprising a nucleic acid probe, primer, or primer pair for detecting the presence of a polynucleotide fusion as claimed in any of claims 1 to 18.

23. A nucleic acid probe, primer, or primer pair for detecting polynucleotide fusions as claimed in claim 8, wherein the detected fusion comprises: - a fusion of VAPB and NRG1, comprising or consisting of SEQ ID NO: 3; - a fusion of CADM1 and NRG1, comprising or consisting of SEQ ID NO: 7; - a fusion of CD44 and NRG1, comprising or consisting of SEQ ID NO: 11; - A fusion of SLC3A2 and NRG1, comprising or consisting of SEQ ID NO: 15; - A fusion of VTCN1 and NRG1, comprising or consisting of SEQ ID NO: 166; - A fusion of CDH1 and NRG1, comprising or consisting of SEQ ID NO: 186; - A fusion of CXADR and NRG1, comprising or consisting of SEQ ID NO: 217; - A fusion of GTF2E2 and NRG1, comprising or consisting of SEQ ID NO: 233; - A fusion of CSMD1 and NRG1, comprising or consisting of SEQ ID NO: 255; - ​​A fusion of PTN and NRG1, comprising or consisting of SEQ ID NO: 313; - A fusion of ST14 and NRG1, comprising or consisting of SEQ ID NO: 330; - A fusion of THBS1 and NRG1, comprising or consisting of SEQ ID NO: 376 or composed of it; - A fusion of AGRN and NRG1, comprising or consisting of SEQ ID NO: 403; - A fusion of PVALB and NRG1, comprising or consisting of SEQ ID NO: 437; - A fusion of SLC3A2 and NRG1, comprising or consisting of SEQ ID NO: 454; - A fusion of APP and NRG1, comprising or consisting of SEQ ID NO: 486; - A fusion of WRN and NRG1, comprising or consisting of SEQ ID NO: 528; - A fusion of DAAM1 and NRG1, comprising or consisting of SEQ ID NO: 605; - A fusion of ASPH and NRG1, comprising or consisting of SEQ ID NO: 635; - A fusion of NOTCH2 and NRG1, comprising or consisting of SEQ ID NO: 693; - A fusion of CD74 and NRG1, comprising or consisting of SEQ ID NO: 717; - A fusion of SDC4 and NRG1, comprising or consisting of SEQ ID NO: 743; - A fusion of CD44 and NRG1, comprising or consisting of SEQ ID NO: 761; - A fusion of SLC4A4 and NRG1, comprising or consisting of SEQ ID NO: 765; - A fusion of SDC4 and NRG1, comprising or consisting of SEQ ID NO:

824. - A fusion of ZFAT and NRG1, comprising or consisting of SEQ ID NO: 828; And – a fusion of DSCAML1 and NRG1, comprising or consisting of SEQ ID NO: 868, wherein: - a probe, primer, or primer pair for detecting the fusion of VAPB and NRG1 specifically hybridizes with a sequence consisting of exon 1 of VAPB or a sequence located at the 5' position of exon 1, and / or specifically hybridizes with a sequence consisting of exon 2 of NRG1 or a sequence located at the 3' position of exon 2, or has 95% or higher complementary sequence identity with such sequences; - a probe, primer, or primer pair for detecting the fusion of CADM1 and NRG1 specifically hybridizes with a sequence consisting of exon 7 of CADM1 or a sequence located at the 5' position of exon 7, and / or specifically hybridizes with a sequence consisting of exon 6 of NRG1 or a sequence located at the 3' position of exon 6, or has 95% or higher complementary sequence identity with such sequences; - a probe, primer, or primer pair for detecting CD44 The probe, primer, or primer pair used to detect the fusion of SLC3A2 transcript 6 with NRG1 specifically hybridizes to a sequence consisting of exon 5 of CD44 or a sequence located at the 5' position of exon 5, and / or specifically hybridizes to a sequence consisting of exon 2 of NRG1 or a sequence located at the 3' position of exon 2, or has 95% or higher complementary sequence identity with such sequences; - The probe, primer, or primer pair used to detect the fusion of SLC3A2 transcript 6 with NRG1 specifically hybridizes to a sequence consisting of exon 1 of SLC3A2 or a sequence located at the 5' position of exon 1, and / or specifically hybridizes to a sequence consisting of exon 5 of NRG1 or a sequence located at the 3' position of exon 5, or has 95% or higher complementary sequence identity with such sequences; The probe, primer, or primer pair used to detect the fusion of VTCN1 and NRG1 specifically hybridizes with a sequence consisting of exon 2 of VTCN1 or a sequence located at the 5' position of exon 2, and / or specifically hybridizes with a sequence consisting of exon 2 of NRG1 or a sequence located at the 3' position of exon 2, or has 95% or higher complementary sequence identity with such sequences; - The probe, primer, or primer pair used to detect the fusion of CDH1 and NRG1 specifically hybridizes with a sequence consisting of exon 11 of CDH1 or a sequence located at the 5' position of exon 11, and / or specifically hybridizes with a sequence consisting of exon 2 of NRG1 or a sequence located at the 3' position of exon 2, or has 95% or higher complementary sequence identity with such sequences;- Probes, primers, or primer pairs used to detect the fusion of CXADR and NRG1 specifically hybridize with a sequence consisting of exon 1 of CXADR or a sequence located at the 5' position of exon 1, and / or specifically hybridize with a sequence consisting of exon 2 of NRG1 or a sequence located at the 3' position of exon 2, or have 95% or higher complementary sequence identity with such sequences; - Probes, primers, or primer pairs used to detect the fusion of GTF2E2 and NRG1 specifically hybridize with a sequence consisting of exon 2 of GTF2E2 or a sequence located at the 5' position of exon 2, and / or specifically hybridize with a sequence consisting of exon 2 of NRG1 or a sequence located at the 3' position of exon 2, or have 95% or higher complementary sequence identity with such sequences; Probes, primers, or primer pairs used to detect the fusion of CSMD1 and NRG1 specifically hybridize with a sequence consisting of exon 23 of CSMD1 or a sequence located at the 5' position of exon 23, and / or specifically hybridize with a sequence consisting of exon 6 of NRG1 or a sequence located at the 3' position of exon 6, or have 95% or higher complementary sequence identity with such sequences; - Probes, primers, or primer pairs used to detect the fusion of PTN and NRG1 specifically hybridize with a sequence consisting of exon 4 of PTN or a sequence located at the 5' position of exon 4, and / or specifically hybridize with a sequence consisting of exon 2 of NRG1 or a sequence located at the 3' position of exon 2, or have 95% or higher complementary sequence identity with such sequences; The probe, primer, or primer pair used to detect the fusion of ST14 and NRG1 specifically hybridizes with a sequence consisting of exon 11 of ST14 or a sequence located at the 5' position of exon 11, and / or specifically hybridizes with a sequence consisting of exon 6 of NRG1 or a sequence located at the 3' position of exon 6, or has 95% or higher complementary sequence identity with such sequences; - The probe, primer, or primer pair used to detect the fusion of THBS1 and NRG1 specifically hybridizes with a sequence consisting of exon 9 of THBS1 or a sequence located at the 5' position of exon 9, and / or specifically hybridizes with a sequence consisting of exon 6 of NRG1 or a sequence located at the 3' position of exon 6, or has 95% or higher complementary sequence identity with such sequences; The probe, primer, or primer pair used to detect the fusion of AGRN and NRG1 specifically hybridizes with a sequence consisting of exon 12 of AGRN or a sequence located at the 5' position of exon 12, and / or specifically hybridizes with a sequence consisting of exon 6 of NRG1 or a sequence located at the 3' position of exon 6, or has 95% or higher complementary sequence identity with such sequences.- Probes, primers, or primer pairs used to detect the fusion of PVALB and NRG1 specifically hybridize with a sequence consisting of exon 4 of PVALB or a sequence located at the 5' position of exon 4, and / or specifically hybridize with a sequence consisting of exon 6 of NRG1 or a sequence located at the 3' position of exon 6, or have 95% or higher complementary sequence identity with such sequences; - Probes, primers, or primer pairs used to detect the fusion of transcript 3 of SLC3A2 and NRG1 specifically hybridize with a sequence consisting of exon 2 of SLC3A2 or a sequence located at the 5' position of exon 2, and / or specifically hybridize with a sequence consisting of exon 6 of NRG1 or a sequence located at the 3' position of exon 6, or have 95% or higher complementary sequence identity with such sequences; Probes, primers, or primer pairs used to detect the fusion of APP and NRG1 specifically hybridize with a sequence consisting of exon 14 of APP or a sequence located at the 5' position of exon 14, and / or specifically hybridize with a sequence consisting of exon 6 of NRG1 or a sequence located at the 3' position of exon 6, or have 95% or higher complementary sequence identity with such sequences; - Probes, primers, or primer pairs used to detect the fusion of WRN and NRG1 specifically hybridize with a sequence consisting of exon 33 of WRN or a sequence located at the 5' position of exon 33, and / or specifically hybridize with a sequence consisting of exon 6 of NRG1 or a sequence located at the 3' position of exon 6, or have 95% or higher complementary sequence identity with such sequences; Probes, primers, or primer pairs used to detect the fusion of DAAM1 and NRG1 specifically hybridize with a sequence consisting of exon 1 of DAAM1 or a sequence located at the 5' position of exon 1, and / or specifically hybridize with a sequence consisting of exon 1 of NRG1 or a sequence located at the 3' position of exon 1, or have 95% or higher complementary sequence identity with such sequences; - Probes, primers, or primer pairs used to detect the fusion of ASPH and NRG1 specifically hybridize with a sequence consisting of exon 22 of ASPH or a sequence located at the 5' position of exon 22, and / or specifically hybridize with a sequence consisting of exon 2 of NRG1 or a sequence located at the 3' position of exon 2, or have 95% or higher complementary sequence identity with such sequences; The probe, primer, or primer pair used to detect the fusion of NOTCH2 and NRG1 specifically hybridizes with a sequence consisting of exon 6 of NOTCH2 or a sequence located at the 5' position of exon 6, and / or specifically hybridizes with a sequence consisting of exon 6 of NRG1 or a sequence located at the 3' position of exon 6, or has 95% or higher complementary sequence identity with such sequences.- Probes, primers, or primer pairs used to detect the fusion of CD74 and NRG1 specifically hybridize with a sequence consisting of exon 2 of CD74 or a sequence located at the 5' position of exon 2, and / or specifically hybridize with a sequence consisting of exon 2 of NRG1 or a sequence located at the 3' position of exon 2, or have 95% or higher complementary sequence identity with such sequences; - Probes, primers, or primer pairs used to detect the fusion of SDC4 and NRG1 specifically hybridize with a sequence consisting of exon 2 of SDC4 or a sequence located at the 5' position of exon 2, and / or specifically hybridize with a sequence consisting of exon 2 of NRG1 or a sequence located at the 3' position of exon 2, or have 95% or higher complementary sequence identity with such sequences; Probes, primers, or primer pairs used to detect the fusion of CD44 and NRG1 specifically hybridize with a sequence consisting of exon 5 of CD44 or a sequence located at the 5' position of exon 5, and / or specifically hybridize with a sequence consisting of exon 6 of NRG1 or a sequence located at the 3' position of exon 6, or have 95% or higher complementary sequence identity with such sequences; - Probes, primers, or primer pairs used to detect the fusion of SLC4A4 and NRG1 specifically hybridize with a sequence consisting of exon 14 of SLC4A4 or a sequence located at the 5' position of exon 14, and / or specifically hybridize with a sequence consisting of exon 6 of NRG1 or a sequence located at the 3' position of exon 6, or have 95% or higher complementary sequence identity with such sequences; The probe, primer, or primer pair used to detect the fusion of SDC4 and NRG1 specifically hybridizes with a sequence consisting of exon 4 of SDC4 or a sequence located at the 5' position of exon 4, and / or specifically hybridizes with a sequence consisting of exon 2 of NRG1 or a sequence located at the 3' position of exon 2, or has 95% or higher complementary sequence identity with such sequences; - The probe, primer, or primer pair used to detect the fusion of ZFAT and NRG1 specifically hybridizes with a sequence consisting of exon 12 of ZFAT or a sequence located at the 5' position of exon 12, and / or specifically hybridizes with a sequence consisting of exon 6 of NRG1 or a sequence located at the 3' position of exon 6, or has 95% or higher complementary sequence identity with such sequences;Or - a probe, primer, or primer pair used to detect the fusion of DSCAML1 and NRG1 specifically hybridizes with a sequence consisting of exon 3 of DSCAML1 or a sequence located at the 5' position of exon 3, and / or specifically hybridizes with a sequence consisting of exon 2 of NRG1 or a sequence located at the 3' position of exon 2, or has 95% or higher complementary sequence identity with such sequences, wherein: - exon 1 from VAPB contains SEQ ID NO: 17 or its opposite gene variant, or is composed of there; - exon 7 from CADM1 contains SEQ ID NO: 39 or its opposite gene variant, or is composed of there; - exon 5 from CD44 contains SEQ ID NO: 65 or its opposite gene variant, or is composed of there; - exon 1 from SLC3A2 contains SEQ ID NO: 103 or its opposite gene variant, or is composed of there; - exon 2 from VTCN1 contains SEQ ID NO: - Exon 11 of CDH1 contains SEQ ID NO: 198 or its dual gene variant, or is composed of it; - Exon 1 of CXADR contains SEQ ID NO: 219 or its dual gene variant, or is composed of it; - Exon 2 of GTF2E2 contains SEQ ID NO: 236 or its dual gene variant, or is composed of it; - Exon 23 of CSMD1 contains SEQ ID NO: 279 or its dual gene variant, or is composed of it; - Exon 4 of PTN contains SEQ ID NO: 318 or its dual gene variant, or is composed of it; - Exon 11 of ST14 contains SEQ ID NO: 342 or its dual gene variant, or is composed of it; - Exon 9 of THBS1 contains SEQ ID NO: 386 or its dual gene variant, or is composed of it; Exon 12 from AGRN contains SEQ ID NO: 416 or its dual gene variant, or is composed of therein; - Exon 4 from PVALB contains SEQ ID NO: 442 or its dual gene variant, or is composed of therein; - Exon 2 from SLC3A2 contains SEQ ID NO: 457 or its dual gene variant, or is composed of therein; - Exon 14 from APP contains SEQ ID NO: 501 or its dual gene variant, or is composed of therein; - Exon 33 from WRN contains SEQ ID NO: 562 or its dual gene variant, or is composed of therein;- Exon 1 from DAAM1 contains SEQ ID NO: 606 or its dual gene variant, or is composed of therein; - Exon 22 from ASPH contains SEQ ID NO: 658 or its dual gene variant, or is composed of therein; - Exon 6 from NOTCH2 contains SEQ ID NO: 700 or its dual gene variant, or is composed of therein; - Exon 2 from CD74 contains SEQ ID NO: 720 or its dual gene variant, or is composed of therein; - Exon 2 from SDC4 contains SEQ ID NO: 746 or its dual gene variant, or is composed of therein; - Exon 5 from CD44 contains SEQ ID NO: 65 or its dual gene variant, or is composed of therein; - Exon 14 from SLC4A4 contains SEQ ID NO: 780 or its dual gene variant, or is composed of therein; - Exon 4 from SDC4 contains SEQ ID NO: - SEQ ID NO: 748 or its dual gene variant, or composed thereof; - Exon 12 from ZFAT containing SEQ ID NO: 841 or its dual gene variant, or composed thereof; - Exon 3 from DSCAML1 containing SEQ ID NO: 872 or its dual gene variant, or composed thereof; and - Exons 1, 2, 5 and 6 from NRG1 containing SEQ ID NO: 125, 126, 129 and 130, respectively, or their dual gene variants, or composed thereof.

24. The nucleic acid probe, primer, or primer pair of claim 23, used for diagnosing an individual’s abnormal cell containing the polynucleotide fusion or a polypeptide encoded therefrom, comprising examining a sample obtained from an individual to detect the presence of the polynucleotide fusion in the sample.

25. A first nucleic acid probe and a second nucleic acid probe for use in an in situ hybridization assay to detect a polynucleotide fusion of any one of claims 1 to 18, wherein: - the first probe specifically hybridizes with the VAPB sequence at position 43 of SEQ ID NO: 3 at the 5' position, and the second probe specifically hybridizes with the NRG1 sequence at position 44 of SEQ ID NO: 3 at the 3' position; - wherein the first probe specifically hybridizes with the CADM1 sequence at position 53 of SEQ ID NO: 7 at the 5' position, and the second probe specifically hybridizes with the NRG1 sequence at position 54 of SEQ ID NO: 7 at the 3' position; - wherein the first probe specifically hybridizes with the CD44 sequence at position 52 of SEQ ID NO: 11 at the 5' position, and the second probe specifically hybridizes with the NRG1 sequence at position 53 of SEQ ID NO: 11 at the 3' position; - wherein the first probe specifically hybridizes with the CADM1 sequence at position 52 of SEQ ID NO: 11 at the 5' position; The first probe hybridizes to the SLC3A2 sequence at position 53 of SEQ ID NO: 15, and the second probe specifically hybridizes to the NRG1 sequence at position 54 of SEQ ID NO: 15, and the second probe specifically hybridizes to the NRG1 sequence at position 66 of SEQ ID NO: 166, and the third probe specifically hybridizes to the VTCN1 sequence at position 65 of SEQ ID NO: 166, and the fourth probe specifically hybridizes to the NRG1 sequence at position 66 of SEQ ID NO: 166, and the fifth probe specifically hybridizes to the CDH1 sequence at position 119 of SEQ ID NO: 186, and the sixth probe specifically hybridizes to the NRG1 sequence at position 120 of SEQ ID NO: 186, and the seventh probe specifically hybridizes to the CXADR sequence at position 43 of SEQ ID NO: 217, and the eighth probe specifically hybridizes to the CXADR sequence at position 43 of SEQ ID NO: 217, and the ninth probe specifically hybridizes to the CXADR sequence at position 43 of SEQ ID NO: 217, and the eleventh ... The first probe hybridizes with the NRG1 sequence at position 44 of SEQ ID NO: 217 at 3' of the nucleic acid; - wherein the first probe specifically hybridizes with the GTF2E2 sequence at position 141 of SEQ ID NO: 233 at 5' of the nucleic acid, and the second probe specifically hybridizes with the NRG1 sequence at position 142 of SEQ ID NO: 233 at 3' of the nucleic acid; - wherein the first probe specifically hybridizes with the CSMD1 sequence at position 88 of SEQ ID NO: 255 at 5' of the nucleic acid, and the second probe specifically hybridizes with the NRG1 sequence at position 89 of SEQ ID NO: 255 at 3' of the nucleic acid;- The first probe specifically hybridizes with the PTN sequence at position 102 of SEQ ID NO: 313 at 5', and the second probe specifically hybridizes with the NRG1 sequence at position 103 of SEQ ID NO: 313 at 3'; - The first probe specifically hybridizes with the ST14 sequence at position 95 of SEQ ID NO: 330 at 5', and the second probe specifically hybridizes with the NRG1 sequence at position 96 of SEQ ID NO: 330 at 3'; - The first probe specifically hybridizes with the THBS1 sequence at position 56 of SEQ ID NO: 376 at 5', and the second probe specifically hybridizes with the NRG1 sequence at position 57 of SEQ ID NO: 376 at 3'; - The first probe specifically hybridizes with the AGRN sequence at position 106 of SEQ ID NO: 403 at 5', and the second probe specifically hybridizes with the ST14 sequence at position 95 of SEQ ID NO: 330 at 3'; The first probe specifically hybridizes with the NRG1 sequence at position 107 of SEQ ID NO: 403; - wherein the first probe specifically hybridizes with the PVALB sequence at position 102 of SEQ ID NO: 437, and the second probe specifically hybridizes with the NRG1 sequence at position 103 of SEQ ID NO: 437; - wherein the first probe specifically hybridizes with the SLC3A2 sequence at position 93 of SEQ ID NO: 454, and the second probe specifically hybridizes with the NRG1 sequence at position 94 of SEQ ID NO: 454; - wherein the first probe specifically hybridizes with the APP sequence at position 54 of SEQ ID NO: 486, and the second probe specifically hybridizes with the NRG1 sequence at position 55 of SEQ ID NO: 486; - wherein the first probe specifically hybridizes with the PVALB sequence at position 102 of SEQ ID NO: 437, and the second probe specifically hybridizes with the NRG1 sequence at position 55 of SEQ ID NO: 486; The first probe hybridizes with the WRN sequence at position 96 of SEQ ID NO: 528 at 5', and the second probe specifically hybridizes with the NRG1 sequence at position 97 of SEQ ID NO: 528 at 3'; wherein the first probe specifically hybridizes with the DAAM1 sequence at position 75 of SEQ ID NO: 605 at 5', and the second probe specifically hybridizes with the NRG1 sequence at position 76 of SEQ ID NO: 605 at 3';- The first probe specifically hybridizes with the ASPH sequence at position 75, 5' of nucleotide in SEQ ID NO: 635, and the second probe specifically hybridizes with the NRG1 sequence at position 76, 3' of nucleotide in SEQ ID NO: 635; - The first probe specifically hybridizes with the NOTCH2 sequence at position 75, 5' of nucleotide in SEQ ID NO: 693, and the second probe specifically hybridizes with the NRG1 sequence at position 76, 3' of nucleotide in SEQ ID NO: 693; - The first probe specifically hybridizes with the CD74 sequence at position 75, 5' of nucleotide in SEQ ID NO: 717, and the second probe specifically hybridizes with the NRG1 sequence at position 76, 3' of nucleotide in SEQ ID NO: 717; - The first probe specifically hybridizes with the SDC4 sequence at position 75, 5' of nucleotide in SEQ ID NO: 743, and the second probe specifically hybridizes with the CD74 sequence at position 75, 5' of nucleotide in SEQ ID NO: 743, and the second probe specifically hybridizes with the CD74 sequence at position 75, 5' of nucleotide in SEQ ID NO: 69 ... The first probe specifically hybridizes with the CD44 sequence located at position 75 of SEQ ID NO: 761, and the second probe specifically hybridizes with the NRG1 sequence located at position 76 of SEQ ID NO: 761, at 3'; the second probe specifically hybridizes with the CD44 sequence located at position 75 of SEQ ID NO: 765, at 5'; the third probe specifically hybridizes with the SLC4A4 sequence located at position 75 of SEQ ID NO: 765, at 5'; the fourth probe specifically hybridizes with the SDC4 sequence located at position 75 of SEQ ID NO: 824, at 5'; the fifth probe specifically hybridizes with the CD44 sequence located at position 75 of SEQ ID NO: 761, at 5'; the sixth probe specifically hybridizes with the CD44 sequence located at position 75 of SEQ ID NO: 761, at 3'; the seventh ... The first probe hybridizes to the ZFAT sequence at position 75 of SEQ ID NO: 828 at the 5' position of nucleic acid, and the second probe specifically hybridizes to the NRG1 sequence at position 76 of SEQ ID NO: 828 at the 3' position of nucleic acid; or - wherein the first probe specifically hybridizes to the DSCAML1 sequence at position 75 of SEQ ID NO: 868 at the 5' position of nucleic acid, and the second probe specifically hybridizes to the NRG1 sequence at position 76 of SEQ ID NO: 868 at the 3' position of nucleic acid.

26. The first and second nucleic acid probes as described in claim 25, for use in in situ hybridization assays to detect the polynucleotide fusion, for examining a sample obtained from an individual to detect the presence of the polynucleotide fusion in the sample.

27. A first antibody or a pair of first and second antibodies for detecting a polypeptide encoded by a polynucleotide fusion as claimed in claim 1.

28. A detection assay comprising a first antibody or a group of first and second antibodies for detecting the presence of a polypeptide encoded by a polynucleotide fusion as claimed in any one of claims 1 to 18.

29. The detection method of claim 28, wherein the first antibody or the first and second antibody group is the first antibody or the first and second antibody group of claim 27.

30. The first antibody or a group of first and second antibodies as claimed in claim 27, wherein the first antibody system binds to a combination of 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, or DSCAML. The first and second antibody assemblies are respectively bound to VAPB and NRG1 or CADM1 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 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.

31. Use of an ErbB-2 and / or ErbB-3 target for the preparation of a medicament for the treatment of an individual with ErbB-2 and ErbB-3 positive cancer or tumor comprising a polynucleotide fusion and / or expressing a fusion polypeptide encoded therefrom, wherein the fusion is a fusion as claimed in any one of claims 1 to 18.

32. Use of zenocutuzumab in the preparation of a medicament for treating an individual with ErbB-2 and ErbB-3 positive cancer or tumor comprising a polynucleotide fusion and / or expressing a fusion polypeptide encoded therefrom, wherein the fusion is a fusion as claimed in any one of claims 1 to 18.

33. A first nucleic acid probe and a second nucleic acid probe for use in in situ hybridization assays 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, wherein: - The first probe for detecting VAPB gene rearrangement specifically hybridizes with the VAPB sequence at position 43 (5') of SEQ ID NO: 1, and the second probe specifically hybridizes with the VAPB sequence at position 43 (3') of SEQ ID NO: 1; - The first probe for detecting CADM1 gene rearrangement specifically hybridizes with the CADM1 sequence at position 53 (5') of SEQ ID NO: 5, and the second probe specifically hybridizes with the CADM1 sequence at position 53 (3') of SEQ ID NO: 5; - The first probe for detecting CD44 gene rearrangement specifically hybridizes with the CD44 sequence at position 52 (5') of SEQ ID NO: 9, and the second probe specifically hybridizes with the CD44 sequence at position 52 (3') of SEQ ID NO: 9; - The first probe for detecting SLC3A2 gene rearrangement specifically hybridizes with the SLC3A2 sequence at position 53 (5') of SEQ ID NO: 13, and the second probe specifically hybridizes with the VAPB sequence at position 53 (3') of SEQ ID NO:

13. The first probe for detecting VTCN1 gene rearrangement specifically hybridizes with the VTCN1 sequence at position 65 (5') of SEQ ID NO: 164, and the second probe specifically hybridizes with the VTCN1 sequence at position 65 (3') of SEQ ID NO: 164; the second probe for detecting CDH1 gene rearrangement specifically hybridizes with the CDH1 sequence at position 119 (5') of SEQ ID NO: 184, and the second probe specifically hybridizes with the CDH1 sequence at position 119 (3') of SEQ ID NO: 184; the third probe for detecting CXADR gene rearrangement specifically hybridizes with the CXADR sequence at position 43 (5') of SEQ ID NO: 215, and the second probe specifically hybridizes with the CXADR sequence at position 43 (3') of SEQ ID NO: 215; The first probe for detecting GTF2E2 gene rearrangement specifically hybridizes with the GTF2E2 sequence at position 141 (5') of SEQ ID NO: 231, and the second probe specifically hybridizes with the GTF2E2 sequence at position 141 (3') of SEQ ID NO: 231; - The first probe for detecting CSMD1 gene rearrangement specifically hybridizes with the CSMD1 sequence at position 88 (5') of SEQ ID NO: 253, and the second probe specifically hybridizes with the CSMD1 sequence at position 88 (3') of SEQ ID NO: 253;- The first probe for detecting PTN gene rearrangements specifically hybridizes with the PTN sequence at position 102 (5') of SEQ ID NO: 311, and the second probe specifically hybridizes with the PTN sequence at position 102 (3') of SEQ ID NO: 311; - The first probe for detecting ST14 gene rearrangements specifically hybridizes with the ST14 sequence at position 95 (5') of SEQ ID NO: 328, and the second probe specifically hybridizes with the ST14 sequence at position 95 (3') of SEQ ID NO: 328; - The first probe for detecting AGRN gene rearrangements specifically hybridizes with the AGRN sequence at position 106 (5') of SEQ ID NO: 401, and the second probe specifically hybridizes with the AGRN sequence at position 106 (3') of SEQ ID NO: 401; - The first probe for detecting THBS1 gene rearrangements specifically hybridizes with the PTN sequence at position 102 (3') of SEQ ID NO: 311; The first probe for detecting PVALB gene rearrangement specifically hybridizes with the PVALB sequence at position 56 of SEQ ID NO: 435 at 5', and the second probe specifically hybridizes with the PVALB sequence at position 102 of SEQ ID NO: 435 at 3', and the second probe specifically hybridizes with the PVALB sequence at position 102 of SEQ ID NO: 435 at 3', and the second probe specifically hybridizes with the PVALB sequence at position 102 of SEQ ID NO: 435 at 3', and the second probe specifically hybridizes with the SLC3A2 sequence at position 93 of SEQ ID NO: 452 at 3', and the second probe specifically hybridizes with the SLC3A2 sequence at position 93 of SEQ ID NO: 452 at 3', and the second probe specifically hybridizes with the APP sequence at position 54 of SEQ ID NO: 484 at 5', and the second probe specifically hybridizes with the APP sequence at position 56 of SEQ ID NO: 484 at 3 ... The first probe for detecting WRN gene rearrangement specifically hybridizes with the WRN sequence at position 96 of SEQ ID NO: 526 at 3'; the second probe specifically hybridizes with the WRN sequence at position 96 of SEQ ID NO: 526 at 3'; the third probe for detecting DAAM1 gene rearrangement specifically hybridizes with the DAAM1 sequence at position 75 of SEQ ID NO: 603 at 3'; the fourth probe specifically hybridizes with the DAAM1 sequence at position 75 of SEQ ID NO: 603 at 3'.- The first probe for detecting ASPH gene rearrangement specifically hybridizes with the ASPH sequence at position 75, 5' of SEQ ID NO: 633, and the second probe specifically hybridizes with the ASPH sequence at position 75, 3' of SEQ ID NO: 633; ​​- The first probe for detecting NOTCH2 gene rearrangement specifically hybridizes with the NOTCH2 sequence at position 75, 5' of SEQ ID NO: 691, and the second probe specifically hybridizes with the NOTCH2 sequence at position 75, 3' of SEQ ID NO: 691; - The first probe for detecting CD74 gene rearrangement specifically hybridizes with the CD74 sequence at position 75, 5' of SEQ ID NO: 715, and the second probe specifically hybridizes with the CD74 sequence at position 75, 3' of SEQ ID NO: 715; - The first probe for detecting SDC4 gene rearrangement specifically hybridizes with the ASPH sequence at position 75, 3' of SEQ ID NO: 633; The first probe for detecting CD44 gene rearrangement specifically hybridizes with the CD44 sequence at position 75 (5') of SEQ ID NO: 741, and the second probe specifically hybridizes with the CD44 sequence at position 75 (3') of SEQ ID NO: 759; the second probe for detecting SLC4A4 gene rearrangement specifically hybridizes with the SLC4A4 sequence at position 75 (5') of SEQ ID NO: 763, and the second probe specifically hybridizes with the SLC4A4 sequence at position 75 (3') of SEQ ID NO: 763; the third probe for detecting SDC4 gene rearrangement specifically hybridizes with the SDC4 sequence at position 75 (5') of SEQ ID NO: 822, and the second probe specifically hybridizes with the CD44 sequence at position 75 (3') of SEQ ID NO: 741; the fourth probe for detecting SDC4 gene rearrangement specifically hybridizes with the SDC4 sequence at position 75 (5') of SEQ ID NO: 822, and the fifth probe specifically hybridizes with the CD44 sequence at position 75 (3') of SEQ ID NO:

741. The first probe for detecting ZFAT gene rearrangement specifically hybridizes with the ZFAT sequence at position 75, 3' of SEQ ID NO: 826, and the second probe specifically hybridizes with the ZFAT sequence at position 75, 3' of SEQ ID NO: 826.Alternatively, the first probe for detecting DSCAML1 gene rearrangements specifically hybridizes with the DSCAML1 sequence at position 75 (5') of SEQ ID NO: 866, and the second probe specifically hybridizes with the DSCAML1 sequence at position 75 (3') of SEQ ID NO: 866.