Novel kinase fusions detected by liquid biopsy

Abstract

Provided herein are kinase fusion nucleic acid molecules and polypeptides, methods related to the detection of kinase fusion nucleic acid molecules and polypeptides in cancer, and related therapeutic methods and uses. Detection of kinase fusion nucleic acid molecules or polypeptides can be used to identify individuals who may benefit from treatment with anti-cancer therapies.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 273,794, filed October 29, 2021, which is incorporated herein by reference in its entirety.

[0002] Electronic Sequence Listing Reference The contents of the electronic sequence listing (197102007640seqlist.xml; size: 78,680 bytes; and creation date: October 26, 2022) are incorporated herein by reference in their entirety.

[0003] Kinase fusion nucleic acid molecules and polypeptides, methods related to the detection of such kinase fusion nucleic acid molecules and polypeptides, and diagnostic / therapeutic methods and uses related thereto, are provided herein. [Background technology]

[0004] Kinases activated by gene fusions are established oncogenic drivers and therapeutic targets, associated with both hematopoietic malignancies and solid tumors. For example, several tyrosine kinase gene fusions (e.g., those of the NTRK family) have been identified across several cancers. Recently, the approval of NTRK inhibitors has led to routine diagnostic testing for NTRK fusions across many cancer types (Cocco et al. (2018) Nat Rev Clin Oncol, 15:731-747).

[0005] Kinase fusions have also been observed in patients after initial treatment with targeted therapy, suggesting that kinase fusions may be an acquired resistance (AR) mechanism and that patients with such fusions may benefit from strategies that target acquired kinase fusions. See, e.g., Xu et al., Cancer Manag Res (2019) 11:6343-51; Piotrowska et al., Cancer Discov (2018) 8(12):1529-39; Schrock et al., J Thorac Oncol (2018) 13(9):1312-23; and Schrock et al., J Thorac Oncol 2019;14(2):255-64).

[0006] Liquid biopsies for genomic profiling have the advantage of being less invasive than traditional tissue biopsies, while potentially providing insight into tumor heterogeneity (Bettegowda et al. (2014) Sci Transl Med, 6:224ra24, Gerlinger et al. (2012) N Engl J Med, 366:883-892, Piotrowska et al. (2015) Cancer Discov, 5:713-722, Diaz et al. (2012) Nature, 486:537-540, Kwak et al. (2015) Cancer Discov, 5:1271-1281, and Russo et al. (2016) Cancer Discov, 6:147-153). However, kinase fusions can be difficult to detect in liquid biopsies, e.g., circulating tumor (ctDNA), with wide variability in tissue and liquid concordance (see, e.g., Paweletz et al. (2016) Clin Cancer Res, 22:915-922; Muller et al. (2017) J Thorac Oncol, 12:1503-1511; Supplee et al. (2019) Lung Cancer, 134:96-99; and Gupta et al. (2020) Oncologist, 25:235-243).

[0007] Thus, there is a need in the art to characterize the pan-cancer landscape of kinase fusions and to develop methods, compositions, and assays for evaluating and treating patients with such fusions, e.g., fusions detected via liquid biopsy (e.g., in ctDNA) and / or tissue biopsy.

[0008] All references cited herein, including patents, patent applications, and publications, are incorporated by reference in their entirety. To the extent that a reference incorporated by reference conflicts with the present disclosure, the present disclosure shall control. Summary of the Invention

[0009] In some aspects, there is provided a method for identifying an individual having cancer that may benefit from treatment, including an anti-cancer therapy, the method comprising detecting, in a sample from the individual, a fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule, wherein (a) the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1; or (b) the fusion nucleic acid molecule is an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2. and the cancer is a cancer corresponding to an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2, wherein detection of the fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule in the sample identifies the individual as one who may benefit from treatment, including anti-cancer therapy.

[0010] In another aspect, there is provided a method for selecting a treatment for an individual having cancer, the method comprising detecting, in a sample from the individual, a fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule, wherein (a) the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1, or (b) the fusion nucleic acid molecule is an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGF1, or ROS1 fusion nucleic acid molecule listed in Table 2. and the cancer is a cancer corresponding to an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2, wherein detection of the fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule in the sample identifies the individual as one who may benefit from treatment, including anti-cancer therapy.

[0011] In another aspect, there is provided a method for identifying one or more treatment options for an individual with cancer, comprising: (a) detecting in a sample from the individual a fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule, wherein (i) the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1; or (ii) the fusion nucleic acid molecule is an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2. or ROS1 fusion nucleic acid molecule, and the cancer is a cancer corresponding to an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2; and (b) generating a report comprising one or more treatment options identified for the individual based at least in part on detection of the fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule in the sample, wherein the one or more treatment options comprise an anti-cancer therapy.

[0012] In another aspect, there is provided a method of identifying one or more treatment options for an individual having cancer, comprising: (a) obtaining knowledge of a fusion nucleic acid molecule or a fusion polypeptide encoded by a fusion nucleic acid molecule in a sample from the individual, wherein (i) the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1; or (ii) the fusion nucleic acid molecule is an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2. 3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule, and the cancer is a cancer corresponding to an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2; and (b) generating a report including one or more treatment options identified for the individual based at least in part on the knowledge, wherein the one or more treatment options include an anti-cancer therapy.

[0013] In another aspect, there is provided a method of selecting a treatment for an individual having cancer, the method comprising obtaining knowledge of a fusion nucleic acid molecule or a fusion polypeptide encoded by a fusion nucleic acid molecule in a sample from the individual, wherein (a) the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1; or (b) the fusion nucleic acid molecule is an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2. and the cancer is a cancer corresponding to an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2, wherein in response to obtaining said knowledge, (i) the individual is classified as a candidate for receiving treatment, including anti-cancer therapy, and / or (ii) the individual is identified as likely to respond to treatment, including anti-cancer therapy.

[0014] In another aspect, there is provided a method of predicting survival of an individual having cancer, the method comprising obtaining knowledge of a fusion nucleic acid molecule or a fusion polypeptide encoded by a fusion nucleic acid molecule in a sample from the individual, wherein (a) the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1, or (b) the fusion nucleic acid molecule is an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, ROS1 fusion nucleic acid molecule listed in Table 2. and the cancer is a cancer corresponding to an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2, wherein in response to obtaining said knowledge, the individual is predicted to have longer survival when treated with a therapy, including an anti-cancer therapy, compared to the survival of an individual having a cancer that does not contain the fusion nucleic acid molecule or the fusion polypeptide encoded by the fusion nucleic acid molecule.

[0015] In another aspect, there is provided a method of predicting survival of an individual having cancer who has been treated with a therapy comprising an anti-cancer therapy, the method comprising obtaining knowledge of a fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule in a sample from the individual, wherein (a) the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1, or (b) the fusion nucleic acid molecule is an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, ME, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2. and the cancer is a cancer corresponding to an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2, wherein in response to obtaining said knowledge, the individual is predicted to have longer survival when treated with a therapy, including an anti-cancer therapy, compared to an individual having a cancer that does not exhibit the fusion nucleic acid molecule or the fusion polypeptide encoded by the fusion nucleic acid molecule.

[0016] In another aspect, a method of treating or slowing the progression of cancer comprises (a) obtaining knowledge of a fusion nucleic acid molecule or a fusion polypeptide encoded by a fusion nucleic acid molecule in a sample from an individual having cancer, wherein (i) the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1, or (ii) the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2. , BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule, and the cancer is a cancer corresponding to an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2; and (b) in response to the knowledge, administering to the individual a treatment comprising an effective amount of an anti-cancer therapy.

[0017] In another aspect, there is provided a method of treating or slowing the progression of cancer, the method comprising administering to an individual having cancer a treatment comprising an effective amount of an anti-cancer therapy, wherein the anti-cancer therapy is administered in response to obtaining knowledge of a fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule in a sample from the individual, wherein (a) the fusion nucleic acid molecule is selected from the group consisting of ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or any of the fusion polypeptides listed in Table 1. or ROS1 fusion nucleic acid molecule; or (b) the fusion nucleic acid molecule is an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2, and the cancer is a cancer corresponding to an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2.

[0018] In another aspect, there is provided a method of monitoring, evaluating, or screening an individual for cancer, the method comprising obtaining knowledge of a fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule in a sample from the individual, wherein (a) the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1, or (b) the fusion nucleic acid molecule is an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2. fusion nucleic acid molecule, and the cancer is a cancer corresponding to an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2, wherein in response to obtaining the knowledge, the individual is predicted to have acquired resistance to a previous anti-cancer therapy administered to the individual, the individual is predicted to respond to the anti-cancer therapy, and / or the individual is predicted to have a poor prognosis compared to an individual having a cancer that does not comprise the fusion nucleic acid molecule or the fusion polypeptide encoded by the fusion nucleic acid molecule.

[0019] In another aspect, there is provided a method for assessing a fusion nucleic acid molecule or fusion polypeptide in cancer in an individual, comprising: (a) detecting a fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule in a sample from the individual, wherein (i) the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1, or (ii) the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2. , ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule, and the cancer is a cancer corresponding to an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2; and (b) providing an evaluation of the fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule.

[0020] In another aspect, provided herein is a method of detecting a fusion nucleic acid molecule or a fusion polypeptide, the method comprising detecting the fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule in a sample from an individual having cancer, wherein (a) the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1, or (b) the fusion nucleic acid molecule is an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2, and the cancer is a cancer corresponding to the ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2.

[0021] In another aspect, a method for detecting the presence or absence of cancer in an individual comprises: (a) detecting the presence or absence of cancer in a sample from the individual; and (b) detecting the presence or absence of a fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule in the sample from the individual, wherein (i) the fusion nucleic acid molecule is selected from the group consisting of an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1. or (ii) the fusion nucleic acid molecule is an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2, and the cancer is a cancer corresponding to an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2. In some embodiments, the method comprises detecting the presence of cancer in a sample from the individual. In some embodiments, the method comprises detecting the presence of the fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule in a sample from the individual.

[0022] In another aspect, there is provided a method for monitoring cancer progression or recurrence in an individual, the method comprising: (a) detecting the presence or absence of a fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule in a first sample obtained from the individual at a first time point; (b) detecting the presence or absence of the fusion nucleic acid molecule or the fusion polypeptide encoded by the fusion nucleic acid molecule in a second sample obtained from the individual at a second time point after the first time point; and (c) providing an assessment of cancer progression or cancer recurrence in the individual based at least in part on the presence or absence of the fusion nucleic acid molecule or the fusion polypeptide encoded by the fusion nucleic acid molecule in the first sample and / or the second sample. and providing a fusion nucleic acid molecule encoding a fusion polypeptide of an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1, wherein (i) the fusion nucleic acid molecule is an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2, and the cancer is a cancer corresponding to an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2. In some embodiments, the presence of the fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule in the first sample and / or the second sample identifies the individual as having an increased risk of cancer progression or cancer recurrence. In some embodiments, the method further includes selecting a treatment for the individual, administering a treatment to the individual, adjusting a treatment for the individual, adjusting a dose of a treatment for the individual, or administering a treatment to the individual based at least in part on detecting the presence of the fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule in the first sample and / or the second sample, wherein the treatment includes an anti-cancer therapy.

[0023] In another aspect, there is provided a method for detecting a fusion nucleic acid molecule, comprising: (a) providing a plurality of nucleic acid molecules obtained from a sample from an individual having cancer, wherein the plurality of nucleic acid molecules comprises nucleic acid molecules corresponding to a fusion nucleic acid molecule, and (i) the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1; or (ii) the fusion nucleic acid molecule is an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2; and the cancer is characterized by an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2. Provided herein are methods comprising: (a) providing a sample containing a cancer corresponding to a ROS1 fusion nucleic acid molecule; (b) optionally ligating one or more adapters onto one or more nucleic acid molecules from a plurality of nucleic acid molecules; (c) optionally amplifying one or more ligated nucleic acid molecules from the plurality of nucleic acid molecules; (d) optionally capturing amplified nucleic acid molecules from the amplified nucleic acid molecules; (e) sequencing the captured nucleic acid molecules with a sequencer to obtain a plurality of sequence reads representing the captured nucleic acid molecules, wherein one or more of the plurality of sequence reads corresponds to the fusion nucleic acid molecule; (f) analyzing the plurality of sequence reads; and (g) detecting the presence or absence of the fusion nucleic acid molecule in the sample based on the analysis. In some embodiments, the method further comprises receiving sequence read data for the plurality of sequence reads at one or more processors. In some embodiments, analyzing the plurality of sequence reads comprises identifying the presence or absence of sequence reads corresponding to the fusion nucleic acid molecule using the one or more processors. In some embodiments, the amplified nucleic acid molecules are captured by hybridization with one or more bait molecules.

[0024] In another aspect, a method for detecting a fusion nucleic acid molecule includes: (a) providing a sample from an individual having cancer, the sample comprising a plurality of nucleic acid molecules; (b) preparing a nucleic acid sequencing library from the plurality of nucleic acid molecules in the sample; (c) amplifying the library; and (d) selectively enriching one or more nucleic acid molecules comprising a nucleotide sequence corresponding to a fusion nucleic acid molecule in the library to produce an enriched sample, wherein: (i) the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1; or (ii) the fusion nucleic acid molecule is a nucleotide sequence selected from the group consisting of ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2. (e) sequencing the enriched sample, thereby generating a plurality of sequence reads; (f) analyzing the plurality of sequence reads for the presence of the fusion nucleic acid molecule; and (g) detecting the presence or absence of the fusion nucleic acid molecule in a sample from the individual based on the analyzing step.

[0025] In some embodiments that may be combined with any of the above aspects or embodiments, the plurality of nucleic acid molecules comprises a mixture of cancer nucleic acid molecules and non-cancer nucleic acid molecules. In some embodiments, the cancer nucleic acid molecules are derived from a tumor portion of a heterogeneous tissue biopsy sample, and the non-cancer nucleic acid molecules are derived from a normal portion of the heterogeneous tissue biopsy sample. In some embodiments, the sample comprises a liquid biopsy sample, wherein the cancer nucleic acid molecules are derived from a circulating tumor DNA (ctDNA) fraction of the liquid biopsy sample, and the non-cancer nucleic acid molecules are derived from a non-tumor and / or cell-free DNA (cfDNA) fraction of the liquid biopsy sample. In some embodiments, the one or more adapters comprise amplification primers, flow cell adapter sequences, substrate adapter sequences, or sample index sequences. In some embodiments, selectively enriching comprises (a) combining one or more bait molecules with the library, thereby hybridizing the one or more bait molecules to one or more nucleic acid molecules comprising nucleotide sequences corresponding to the fusion nucleic acid molecules to produce nucleic acid hybrids, and (b) isolating the nucleic acid hybrids to produce an enriched sample. In some embodiments, the captured nucleic acid molecules are captured from amplified nucleic acid molecules by hybridization to one or more bait molecules. In some embodiments, amplifying comprises performing a polymerase chain reaction (PCR) amplification technique, a non-PCR amplification technique, or an isothermal amplification technique. In some embodiments, sequencing comprises using a massively parallel sequencing (MPS) technique, whole genome sequencing (WGS), whole exome sequencing, targeted sequencing, direct sequencing, or Sanger sequencing technique. In some embodiments, sequencing comprises a massively parallel sequencing technique, which comprises next-generation sequencing (NGS). In some embodiments, sequencing comprises a next-generation sequencer. In some embodiments, the method further comprises generating a genomic profile for the individual based at least in part on detecting the presence or absence of the fusion nucleic acid molecule. In some embodiments, the genomic profile for the individual further comprises results from a comprehensive genomic profiling (CGP) test, a gene expression profiling test, a cancer hotspot panel test, a DNA methylation test, a DNA fragmentation test, an RNA fragmentation test, or any combination thereof.In some embodiments, the genomic profile for the individual further comprises results from a nucleic acid sequencing-based test. In some embodiments, the method further comprises selecting a treatment for the individual, administering a treatment to the individual, or administering a treatment to the individual based on the generated genomic profile, wherein the treatment comprises an anti-cancer therapy. In some embodiments, the method further comprises generating a report indicating the presence or absence of the fusion nucleic acid molecule in the sample. In some embodiments, the method further comprises generating, by the one or more processors, a report indicating the presence or absence of the fusion nucleic acid molecule in the sample. In some embodiments, the method further comprises transmitting the report to a healthcare provider. In some embodiments, the report is transmitted via a computer network or a peer-to-peer connection.

[0026] In another aspect, there is provided a method of identifying candidate treatments for cancer in an individual in need thereof, the method comprising performing DNA sequencing on a sample obtained from the individual to determine a sequencing mutation profile in a group of genes comprising one or more of ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1, or any combination thereof, wherein the sequencing mutation profile identifies the presence or absence of a fusion nucleic acid molecule, and wherein (a) the fusion nucleic acid molecule is selected from the group consisting of ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1, or any combination thereof.

[0013] Provided herein are methods wherein (a) the fusion nucleic acid molecule is a BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule; or (b) the fusion nucleic acid molecule is an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2, and the cancer is a cancer corresponding to an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2. In some embodiments, the candidate treatment comprises an anti-cancer therapy. In some embodiments, the presence of the fusion nucleic acid molecule in the sample identifies the individual as one who may benefit from a treatment comprising an anti-cancer therapy. In some embodiments, the presence of the fusion nucleic acid molecule in the sample predicts that the individual will have a longer survival when treated with a therapy, including an anti-cancer therapy, compared to the survival of an individual with a cancer that does not contain the fusion nucleic acid molecule. In some embodiments, the sequencing comprises the use of massively parallel sequencing (MPS) techniques, whole genome sequencing (WGS), whole exome sequencing, targeted sequencing, direct sequencing, or Sanger sequencing techniques. In some embodiments, the sequencing comprises massively parallel sequencing techniques, which comprise next-generation sequencing (NGS). In some embodiments, the sequencing mutation profile identifies the presence or absence of fragments of the fusion nucleic acid molecule, including breakpoints or fusion junctions.

[0027] In another aspect, there is provided a method of treating or slowing the progression of cancer, comprising: (a) detecting a fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule in a sample from an individual with cancer, wherein (i) the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1; or (ii) the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2. Provided herein are methods comprising (a) detecting an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule, and the cancer is a cancer corresponding to an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2; and (b) administering to the individual a treatment comprising an effective amount of an anti-cancer therapy.

[0028] In some embodiments that may be combined with any of the preceding aspects or embodiments, the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1, and the ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1 comprises or results from breakpoint 1 and / or breakpoint 2 corresponding to the ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 3.

[0029] In some embodiments that may be combined with any of the preceding aspects or embodiments, the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1, and the cancer is carcinoma, sarcoma, lymphoma, leukemia, myeloma, germ cell cancer, or blastoma.

[0030] In some embodiments that may be combined with any of the preceding aspects or embodiments, the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1, and the cancer is a solid tumor.

[0031] In some embodiments that may be combined with any of the preceding aspects or embodiments, the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1, and the cancer is a hematological malignancy.

[0032] In some embodiments that may be combined with any of the above aspects or embodiments, the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1, and the cancer is B-cell cancer, melanoma, breast cancer, lung cancer, bronchial cancer, colorectal cancer, prostate cancer, pancreatic cancer, stomach cancer, ovarian cancer, urinary bladder cancer, brain cancer, central nervous system cancer, peripheral nervous system cancer, esophageal cancer, cervical cancer, uterine cancer, endometrial cancer, oral cavity cancer, pharyngeal cancer, liver cancer, kidney cancer, testicular cancer, biliary tract cancer, small intestine cancer, appendix cancer, salivary gland cancer, thyroid cancer, or the like. cancer), adrenal cancer, osteosarcoma, chondrosarcoma, cancer of the blood tissue, adenocarcinoma, inflammatory myofibroblastic tumor, gastrointestinal stromal tumor (GIST), colon cancer, multiple myeloma (MM), myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), polycythemia vera, Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL) ), soft tissue sarcoma, fibrosarcoma, myxosarcoma, liposarcoma, osteosarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, medullary carcinoma, bronchogenic lung carcinoma, renal cell carcinoma, hepatocellular carcinoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, bladder cancer carcinoma), epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, retinoblastoma, follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, hepatocellular carcinoma, thyroid cancer, gastric cancer, head and neck cancer, small cell carcinoma, essential thrombocythemia, primary myelofibrosis, hypereosinophilic syndrome, systemic mastocytosis, familial hypereosinophilia, chronic eosinophilic leukemia, neuroendocrine carcinoma, or carcinoid tumor.

[0033] In some embodiments that may be combined with any of the preceding aspects or embodiments, the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1, and the cancer is appendix adenocarcinoma, bladder adenocarcinoma, bladder urothelial (transitional cell) carcinoma, not otherwise specified (NOS) breast cancer, NOS breast cancer, carcinoma), invasive ductal carcinoma (IDC), invasive lobular carcinoma of the breast (ILC), cervical squamous cell carcinoma (SCC), colon adenocarcinoma (CRC), esophageal adenocarcinoma, NOS esophageal carcinoma, esophageal squamous cell carcinoma (SCC), intraocular melanoma, gallbladder adenocarcinoma, gastroesophageal junction adenocarcinoma, intrahepatic cholangiocarcinoma, NOS kidney cancer, hepatocellular carcinoma (HCC), NOS lung cancer, lung adenocarcinoma, lung large cell carcinoma, NOS non-small cell lung cancer (NSCLC), lung undifferentiated small cell alveolar carcinoma, lung squamous cell carcinoma (SCC), NOS ovarian cancer, NOS pancreatic cancer, pancreatic ductal adenocarcinoma, pancreaticobiliary carcinoma, NOS prostate cancer, prostatic acinar adenocarcinoma, prostatic ductal adenocarcinoma, rectal adenocarcinoma (CRC), cutaneous melanoma, small intestine adenocarcinoma, NOS soft tissue sarcoma, NOS gastric adenocarcinoma, NOS carcinoma of unknown primary, adenocarcinoma of unknown primary, NOS carcinoma of unknown primary (CUP), neuroendocrine tumor of unknown primary, squamous cell carcinoma (SCC) of unknown primary, or NOS endometrial adenocarcinoma.

[0034] In some embodiments that may be combined with any of the preceding aspects or embodiments, the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1, and the cancer is a cancer corresponding to an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 4.

[0035] In some embodiments that may be combined with any of the preceding aspects or embodiments, the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1; the cancer is a cancer corresponding to an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 5; and the fusion nucleic acid molecule comprises or results from breakpoint 1 and / or breakpoint 2 corresponding to an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 5.

[0036] In some embodiments that may be combined with any of the preceding aspects or embodiments, the fusion nucleic acid molecule is an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2, the cancer is a cancer corresponding to an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2, and the fusion nucleic acid molecule comprises or results from breakpoint 1 and / or breakpoint 2 corresponding to an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 6.

[0037] In some embodiments that may be combined with any of the above aspects or embodiments, the fusion polypeptide encoded by the fusion nucleic acid molecule is oncogenic. In some embodiments that may be combined with any of the above aspects or embodiments, the fusion polypeptide encoded by the fusion nucleic acid molecule promotes cancer cell survival, angiogenesis, cancer cell proliferation, and any combination thereof.

[0038] In some embodiments that may be combined with any of the above aspects or embodiments, the anticancer therapy is a small molecule inhibitor, an antibody, a cell therapy, a nucleic acid, a virus-based therapy, an antibody-drug conjugate, a recombinant protein, a fusion protein, a natural compound, a peptide, a targeted proteolysis chimera (PROTAC), a treatment for cancer comprising a fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule, a treatment for cancer being tested in a clinical trial, a targeted therapy, a treatment for cancer being tested in a clinical trial comprising a fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule, or any combination thereof. In some embodiments, the cell therapy is adoptive therapy, T cell-based therapy, natural killer (NK) cell-based therapy, chimeric antigen receptor (CAR) T cell therapy, recombinant T cell receptor (TCR) T cell therapy, macrophage-based therapy, induced pluripotent stem cell-based therapy, B cell-based therapy, or dendritic cell (DC)-based therapy. In some embodiments, the nucleic acid inhibits expression of the fusion nucleic acid molecule or the fusion polypeptide encoded by the fusion nucleic acid molecule. In some embodiments, the nucleic acid comprises double-stranded RNA (dsRNA), small interfering RNA (siRNA), or small hairpin RNA (shRNA).

[0039] In some embodiments that may be combined with any of the above aspects or embodiments, the anticancer therapy is a kinase inhibitor, hi some embodiments, the kinase inhibitor is a multikinase inhibitor or a specific inhibitor of ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, NTRK1, RET, or ROS1.

[0040] In some embodiments that may be combined with any of the preceding aspects or embodiments, the method further comprises obtaining knowledge of or detecting, in a sample from the individual, base substitutions, short insertions / deletions (indels), copy number changes, or genomic rearrangements in one or more genes.

[0041] In some embodiments that may be combined with any of the above aspects or embodiments, the individual has received a previous anti-cancer treatment or is currently being treated with an anti-cancer treatment. In some embodiments, the fusion nucleic acid molecule and / or the fusion polypeptide encoded by the fusion nucleic acid molecule confers resistance of the cancer to the anti-cancer treatment. In some embodiments, the anti-cancer treatment is a small molecule inhibitor, an antibody, a cell therapy, a nucleic acid, a virus-based therapy, an antibody-drug conjugate, a recombinant protein, a fusion protein, a natural compound, a peptide, a targeted proteolytic chimera (PROTAC), a treatment for cancer being tested in a clinical trial, immunotherapy, chemotherapy, targeted therapy, or any combination thereof. In some embodiments, the cell therapy is adoptive therapy, T cell-based therapy, natural killer (NK) cell-based therapy, chimeric antigen receptor (CAR) T cell therapy, recombinant T cell receptor (TCR) T cell therapy, macrophage-based therapy, induced pluripotent stem cell-based therapy, B cell-based therapy, or dendritic cell (DC)-based therapy. In some embodiments, the nucleic acid comprises double-stranded RNA (dsRNA), small interfering RNA (siRNA), or small hairpin RNA (shRNA).

[0042] In some embodiments that may be combined with any of the above aspects or embodiments, the fusion nucleic acid molecule is an ALK fusion nucleic acid molecule listed in any of Tables 1-6. In some embodiments, the ALK fusion nucleic acid molecule encodes an ALK fusion polypeptide. In some embodiments, the encoded ALK fusion polypeptide comprises an ALK kinase domain or a fragment of the ALK kinase domain that has ALK kinase activity. In some embodiments, the encoded ALK fusion polypeptide has ALK kinase activity, optionally, the ALK kinase activity is constitutive. In some embodiments, the encoded ALK fusion polypeptide is oncogenic. In some embodiments, the encoded ALK fusion polypeptide promotes cancer cell survival, angiogenesis, cancer cell proliferation, and any combination thereof.In some embodiments, the method comprises detecting in a sample from the individual: (a) a mutation in the EGFR gene, optionally a deletion of exon 19 or a portion thereof of EGFR, a mutation resulting in a L858R, R748K, T790M, C797S, and / or D761N amino acid substitution in the encoded EGFR polypeptide, an EGFR gene amplification, or any combination thereof; (b) a mutation in the BRAF gene, optionally a mutation resulting in a V600E amino acid substitution in the encoded BRAF polypeptide; (c) a mutation in the NRAS gene, optionally a mutation resulting in a Q61H amino acid substitution in the encoded NRAS polypeptide; (d) a mutation in the MET gene, optionally a MET gene amplification, a mutation resulting in a D1228H amino acid substitution in the encoded MET polypeptide, or both; (e) a mutation in the NF1 gene, optionally an NF1 truncation; or (f) a wild-type KRAS (g) a mutation in the MAP2K1 gene, optionally resulting in a G12V and / or A146P amino acid substitution in the encoded KRAS polypeptide; (g) a mutation in the MAP2K1 gene, optionally resulting in a I103_K104del mutation in the encoded MAP2K1 polypeptide; (h) an ALK mutation, optionally the ALK mutation is an ALK-resistant mutation, and optionally the ALK-resistant mutation is a mutation in the encoded ALK polypeptide. or any combination thereof; or obtaining knowledge of the presence of or detecting the presence of any combination of (a)-(h).In some embodiments, the method further comprises obtaining knowledge of or detecting the presence of a mutation in the EGFR gene, optionally resulting in an L858R amino acid substitution in the encoded EGFR polypeptide, in a sample from the individual, wherein the ALK fusion nucleic acid molecule is an ALK-PLEKHA7 fusion nucleic acid molecule listed in Table 2 or 6. In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments that may be combined with any of the above aspects or embodiments, the individual has previously received cancer treatment with erlotinib, afatinib, and / or osimertinib. In some embodiments, the individual has shown a partial response to treatment with erlotinib, and / or the individual has shown a partial response to treatment with osimertinib. In some embodiments, the fusion nucleic acid molecule and / or the fusion polypeptide encoded by the fusion nucleic acid molecule confers resistance of the cancer to an EGFR-targeted anti-cancer therapy, and optionally the EGFR-targeted anti-cancer therapy is a first-, second-, or third-generation EGFR tyrosine kinase inhibitor. In some embodiments, the fusion nucleic acid molecule and / or the fusion polypeptide encoded by the fusion nucleic acid molecule confers resistance of a cancer to an EGFR-targeted anti-cancer therapy, optionally wherein the EGFR-targeted anti-cancer therapy is cetuximab, panitumumab, lapatinib, gefitinib, vandetanib, dacomitinib, icotinib, osimertinib (AZD9291), afatanib, olmutinib, EGF816 (nazartinib), avitinib (AC0010), rociletinib (CO-1686), BMS-690514, YH5448, PF-06747775, ASP8273, PF299804, AP26113, or erlotinib. In some embodiments, the fusion nucleic acid molecule and / or the fusion polypeptide encoded by the fusion nucleic acid molecule confers resistance of the cancer to NF1-targeted anti-cancer therapy.In some embodiments, the method further comprises obtaining knowledge of or detecting the presence of, in a sample from the individual: (a) an ALK-resistance mutation, optionally resulting in a V1180L, I1171N, L1196M, D1203N, or I1171T amino acid substitution in the encoded ALK polypeptide, or any combination thereof; and / or (b) a mutation in the KRAS gene, optionally resulting in a G12V amino acid substitution in the encoded KRAS polypeptide, wherein the ALK fusion nucleic acid molecule is an ALK-HIP1 fusion nucleic acid molecule listed in Table 2 or 6. In some embodiments, the sample comprises one or more ALK gene mutations that result in a V1180L and I1171N amino acid substitution in the encoded ALK polypeptide, or a D1203N and I1171T amino acid substitution in the encoded ALK polypeptide. In some embodiments, the sample contains a mutation in the KRAS gene, optionally resulting in a G12V amino acid substitution in the encoded KRAS polypeptide. In some embodiments, the cancer is carcinoma of unknown primary origin. In some embodiments, the anti-cancer therapy is an ALK-targeted therapy. In some embodiments, the ALK-targeted therapy is a small molecule inhibitor, an antibody, a cell therapy, a nucleic acid, a virus-based therapy, an antibody-drug conjugate, a recombinant protein, a fusion protein, a natural compound, a peptide, a targeted proteolysis chimera (PROTAC), a treatment for ALK-positive or ALK-rearranged cancer, an ALK-targeted therapy being tested in a clinical trial, a treatment for ALK-positive or ALK-rearranged cancer being tested in a clinical trial, or any combination thereof. In some embodiments, the ALK-targeted therapy is a kinase inhibitor. In some embodiments, the ALK-targeted therapy is a tyrosine kinase inhibitor. In some embodiments, the ALK-targeted therapy is a multi-kinase inhibitor or an ALK-specific inhibitor. In some embodiments, the kinase inhibitor inhibits the kinase activity of the ALK polypeptide.In some embodiments, the ALK targeted therapy is selected from the group consisting of crizotinib, alectinib, ceritinib, lorlatinib, brigutinib, ensartinib (X-396), repotrectinib (TPX-005), entrectinib (RXDX-101), AZD3463, CEP-37440, belizatinib (TSR-011), ASP3026, KRCA-0008, The nucleic acid may comprise one or more of TQ-B3139, TPX-0131, TAE684 (NVP-TAE684), CT-707, WX-0593, alcotinib, SIM1803-1A, PLB1003, SAF-189s, PF03446962, TQ-B3101, APG-2449, X-376, CEP-28122, and GSK1838705A. In some embodiments, the nucleic acid inhibits expression of an ALK fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule. In some embodiments, the nucleic acid is double-stranded RNA (dsRNA), small interfering RNA (siRNA), or short hairpin RNA (shRNA). In some embodiments, the cell therapy is adoptive therapy, T cell-based therapy, natural killer (NK) cell-based therapy, chimeric antigen receptor (CAR) T cell therapy, recombinant T cell receptor (TCR) T cell therapy, macrophage-based therapy, induced pluripotent stem cell-based therapy, B cell-based therapy, or dendritic cell (DC)-based therapy.

[0043] In some embodiments that may be combined with any of the above aspects or embodiments, the fusion nucleic acid molecule is a BRAF fusion nucleic acid molecule listed in any of Tables 1-6. In some embodiments, the BRAF fusion nucleic acid molecule encodes a BRAF fusion polypeptide. In some embodiments, the encoded BRAF fusion polypeptide comprises a BRAF kinase domain or a fragment of a BRAF kinase domain that has BRAF kinase activity. In some embodiments, the encoded BRAF fusion polypeptide has BRAF kinase activity, optionally, the BRAF kinase activity is constitutive. In some embodiments, the encoded BRAF fusion polypeptide is oncogenic. In some embodiments, the encoded BRAF fusion polypeptide promotes cancer cell survival, angiogenesis, cancer cell proliferation, and any combination thereof.In some embodiments, the method comprises detecting in a sample from the individual: (a) a mutation in the EGFR gene, optionally resulting in EGFR gene amplification and / or a V441G, S492R, and / or G465E / R amino acid substitution in the encoded EGFR polypeptide; (b) a wild-type KRAS gene, or a mutation in the KRAS gene, optionally resulting in a G12F, G12V, G12C, G13D, and / or Q61H amino acid substitution in the encoded KRAS polypeptide; (c) a mutation in the NRAS gene, optionally resulting in a G13D and / or Q61K / L amino acid substitution in the encoded NRAS polypeptide; (d) a mutation in the MET gene, optionally resulting in a MET gene amplification; or (e) a mutation in the MAP2K1 gene, (f) a mutation in the MAP2K2 gene, optionally resulting in a Q58del or E102_I103del mutation, and / or an I111T or K57T amino acid substitution in the encoded MAP2K1 polypeptide; (f) a mutation in the MAP2K2 gene, optionally resulting in a F57V amino acid substitution in the encoded MAP2K2 polypeptide; (g) a mutation in the NF1 gene, optionally being a F945fs*9 mutation; (h) a mutation in the BRAF gene, optionally resulting in a V600E amino acid substitution in the encoded BRAF polypeptide; and / or (i) a mutation in the HRAS gene, optionally resulting in a Q61L amino acid substitution in the encoded HRAS polypeptide. In some embodiments, the method further comprises obtaining knowledge of or detecting the presence of, in a sample from the individual: EGFR gene amplification; and a wild-type KRAS gene or a KRAS gene mutation resulting in a G12F and / or a Q61H amino acid substitution in the encoded KRAS polypeptide, wherein the BRAF fusion nucleic acid molecule is a BRAF-SND1 fusion nucleic acid molecule listed in Table 2 or 6.In some embodiments, the method further comprises obtaining knowledge of or detecting the presence of, in a sample from the individual: a mutation in the EGFR gene resulting in a V441G and / or G465E / R amino acid substitution in the encoded EGFR polypeptide; a wild-type KRAS gene or a KRAS gene mutation resulting in a G12C amino acid substitution in the encoded KRAS polypeptide; a mutation in the NRAS gene resulting in a G13D and / or Q61K amino acid substitution in the encoded NRAS polypeptide; and a MET gene amplification, wherein the BRAF fusion nucleic acid molecule is a BRAF-ZC3HAV1 fusion nucleic acid molecule listed in Table 2 or 6. In some embodiments, the method further comprises obtaining knowledge of or detecting the presence, in a sample from the individual, of a mutation in the EGFR gene that results in a S492R amino acid substitution in the encoded EGFR polypeptide; a wild-type KRAS gene, or a mutation in the KRAS gene, optionally resulting in a G12V and / or a Q61H amino acid substitution in the encoded KRAS polypeptide; a mutation in the NRAS gene that results in a Q61K / L amino acid substitution in the encoded NRAS polypeptide; a mutation in the MAP2K1 gene that results in a Q58del mutation and / or an I111T amino acid substitution in the encoded MAP2K1 polypeptide; a mutation in the MAP2K2 gene that results in a F57V amino acid substitution in the encoded MAP2K2 polypeptide; and a F945fs*9 mutation in the NF1 gene, wherein the BRAF fusion nucleic acid molecule is a BRAF-MKRN1 fusion nucleic acid molecule listed in Table 2 or 6. In some embodiments, the method further comprises obtaining knowledge of or detecting the presence of a mutation in the KRAS gene that results in a G13D amino acid substitution in the encoded KRAS polypeptide, wherein the BRAF fusion nucleic acid molecule is a BRAF-DENND2A fusion nucleic acid molecule listed in Table 2 or 6. In some embodiments, the cancer has been previously treated with folinic acid, fluorouracil (5-FU), and oxaliplatin (FOLFOX); 5-FU; folinic acid, 5-FU, and irinotecan (FOLFIRI); and / or regorafenib.In some embodiments, the method further comprises obtaining knowledge of or detecting the presence of, in a sample from the individual, a wild-type KRAS gene; and a mutation in the NRAS gene that results in a Q61K amino acid substitution in the encoded NRAS polypeptide, wherein the BRAF fusion nucleic acid molecule is a BRAF-TRIM24 fusion nucleic acid molecule listed in Table 2 or 6. In some embodiments, the cancer is colorectal cancer. In some embodiments, the method further comprises obtaining knowledge of or detecting the presence, in a sample from the individual, of a mutation in the BRAF gene resulting in a V600E amino acid substitution in the encoded BRAF polypeptide; a mutation in the EGFR gene resulting in a S492R and / or V441G amino acid substitution in the encoded EGFR polypeptide; a wild-type KRAS gene; a mutation in the HRAS gene resulting in a Q61L amino acid substitution in the encoded HRAS polypeptide; a mutation in the MAP2K1 gene resulting in an E102_I103del mutation and / or a K57T amino acid substitution in the encoded MAP2K1 polypeptide; and a mutation in the NRAS gene resulting in a Q61K amino acid substitution in the encoded NRAS polypeptide, wherein the BRAF fusion nucleic acid molecule is a BRAF-GOLGA3 fusion nucleic acid molecule listed in any of Tables 1 and 3-5. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer has been previously treated with 5-FU; a combination of folinic acid, 5-FU, and irinotecan (FOLFIRI) with bevacizumab; a combination of FOLFIRI with cetuximab; a combination of folinic acid, 5-FU, and oxaliplatin (FOLFOX) with bevacizumab; and / or a combination of pembrolizumab and regorafenib.In some embodiments, the method further comprises obtaining knowledge of or detecting the presence of, in a sample from the individual, a mutation in the KRAS gene resulting in a G12C and / or G13D amino acid substitution in the encoded KRAS polypeptide; a mutation in the MAP2K1 gene resulting in an E102_I103del mutation in the encoded MAP2K1 polypeptide; and a mutation in the NRAS gene resulting in a Q61K amino acid substitution in the encoded NRAS polypeptide, wherein the BRAF fusion nucleic acid molecule is a BRAF-AKAP9 fusion nucleic acid molecule listed in Table 2 or 6. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer has previously been treated with adagrasib, or a combination of adagrasib and cetuximab. In some embodiments, the fusion nucleic acid molecule and / or the fusion polypeptide encoded by the fusion nucleic acid molecule confers resistance of the cancer to an EGFR-targeted anticancer therapy, optionally, the EGFR-targeted anticancer therapy is a first-, second-, or third-generation EGFR tyrosine kinase inhibitor. In some embodiments, the fusion nucleic acid molecule and / or the fusion polypeptide encoded by the fusion nucleic acid molecule confers resistance of a cancer to an EGFR-targeted anti-cancer therapy, optionally wherein the EGFR-targeted anti-cancer therapy is cetuximab, panitumumab, lapatinib, gefitinib, vandetanib, dacomitinib, icotinib, osimertinib (AZD9291), afatanib, olmutinib, EGF816 (nazartinib), avitinib (AC0010), rociletinib (CO-1686), BMS-690514, YH5448, PF-06747775, ASP8273, PF299804, AP26113, or erlotinib. In some embodiments, the anti-cancer therapy is a BRAF-targeted therapy. In some embodiments, the BRAF targeted therapy is a small molecule inhibitor, an antibody, a cell therapy, a nucleic acid, a viral-based therapy, an antibody-drug conjugate, a recombinant protein, a fusion protein, a natural compound, a peptide, a targeted proteolysis chimera (PROTAC), a treatment for a BRAF-rearranged cancer, a BRAF-targeted therapy being tested in a clinical trial, a treatment for a BRAF-rearranged cancer being tested in a clinical trial, or any combination thereof.In some embodiments, the BRAF targeted therapy is a kinase inhibitor. In some embodiments, the BRAF targeted therapy is a serine / threonine kinase inhibitor. In some embodiments, the BRAF targeted therapy is a multikinase inhibitor or a BRAF-specific inhibitor. In some embodiments, the kinase inhibitor inhibits the kinase activity of a BRAF polypeptide. In some embodiments, the BRAF targeted therapy comprises one or more of sorafenib, PLX4720, PLX-3603, dabrafenib (GSK2118436), encorafenib (LGX818), GDC-0879, RAF265, XL281, ARQ736, BAY73-4506, vemurafenib, cobimetinib, binimetinib, regorafenib, selumetinib, trametinib, or BAY 43-9006. In some embodiments, the nucleic acid inhibits expression of a BRAF fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule. In some embodiments, the nucleic acid is double-stranded RNA (dsRNA), small interfering RNA (siRNA), or small hairpin RNA (shRNA). In some embodiments, the cell therapy is adoptive therapy, T cell-based therapy, natural killer (NK) cell-based therapy, chimeric antigen receptor (CAR) T cell therapy, recombinant T cell receptor (TCR) T cell therapy, macrophage-based therapy, induced pluripotent stem cell-based therapy, B cell-based therapy, or dendritic cell (DC)-based therapy.

[0044] In some embodiments that may be combined with any of the above aspects or embodiments, the fusion nucleic acid molecule is an EGFR fusion nucleic acid molecule listed in any of Tables 1 and 3-5. In some embodiments, the EGFR fusion nucleic acid molecule encodes an EGFR fusion polypeptide. In some embodiments, the encoded EGFR fusion polypeptide comprises an EGFR kinase domain or a fragment of an EGFR kinase domain having EGFR kinase activity. In some embodiments, the encoded EGFR fusion polypeptide has EGFR kinase activity, optionally, the EGFR kinase activity is constitutive. In some embodiments, the encoded EGFR fusion polypeptide is oncogenic. In some embodiments, the encoded EGFR fusion polypeptide promotes cancer cell survival, angiogenesis, cancer cell proliferation, and any combination thereof. In some embodiments, the method further comprises obtaining knowledge of or detecting the presence of, in a sample from the individual: (a) a wild-type KRAS gene, or a mutation in the KRAS gene, optionally resulting in a G12A and / or Q61H amino acid substitution in the encoded KRAS polypeptide; (b) a mutation in the NRAS gene, optionally resulting in a G12D amino acid substitution in the encoded NRAS polypeptide; and / or (c) a mutation in the MAP2K1 gene, optionally resulting in an E102_I103del mutation in the encoded MAP2K1 polypeptide. In some embodiments, the method further comprises obtaining knowledge of or detecting the presence, in a sample from the individual, of a wild-type KRAS gene, or a mutation in the KRAS gene that results in a G12A and / or Q61H amino acid substitution in the encoded KRAS polypeptide; a mutation in the NRAS gene that results in a G12D amino acid substitution in the encoded NRAS polypeptide; and / or a mutation in the MAP2K1 gene that results in an E102_I103del mutation in the encoded MAP2K1 polypeptide, wherein the fusion nucleic acid molecule is an EGFR-PDE7A fusion nucleic acid molecule listed in any of Tables 1 and 3-5.In some embodiments, the anti-cancer therapy is an EGFR-targeted therapy. In some embodiments, the EGFR-targeted therapy is a small molecule inhibitor, an antibody, a cell therapy, a nucleic acid, a virus-based therapy, an antibody-drug conjugate, a recombinant protein, a fusion protein, a natural compound, a peptide, a targeted proteolysis chimera (PROTAC), a treatment for an EGFR-rearranged cancer, an EGFR-targeted therapy being tested in a clinical trial, a treatment for an EGFR-rearranged cancer being tested in a clinical trial, or any combination thereof. In some embodiments, the EGFR-targeted therapy is a kinase inhibitor. In some embodiments, the EGFR-targeted therapy is a tyrosine kinase inhibitor. In some embodiments, the EGFR-targeted therapy is a multi-kinase inhibitor or an EGFR-specific inhibitor. In some embodiments, the kinase inhibitor inhibits the kinase activity of an EGFR polypeptide. In some embodiments, the EGFR targeted therapy comprises one or more of cetuximab, panitumumab, lapatinib, gefitinib, vandetanib, dacomitinib, icotinib, osimertinib (AZD9291), afatanib, olmutinib, EGF816 (nazartinib), avitinib (AC0010), rociletinib (CO-1686), BMS-690514, YH5448, PF-06747775, ASP8273, PF299804, AP26113, necitumumab, or erlotinib. In some embodiments, the nucleic acid inhibits expression of an EGFR fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule. In some embodiments, the nucleic acid is double-stranded RNA (dsRNA), small interfering RNA (siRNA), or small hairpin RNA (shRNA). In some embodiments, the cell therapy is adoptive therapy, T cell-based therapy, natural killer (NK) cell-based therapy, chimeric antigen receptor (CAR) T cell therapy, recombinant T cell receptor (TCR) T cell therapy, macrophage-based therapy, induced pluripotent stem cell-based therapy, B cell-based therapy, or dendritic cell (DC)-based therapy.

[0045] In some embodiments that may be combined with any of the above aspects or embodiments, the fusion nucleic acid molecule is an ERBB2 fusion nucleic acid molecule listed in any of Tables 1-6. In some embodiments, the ERBB2 fusion nucleic acid molecule encodes an ERBB2 fusion polypeptide. In some embodiments, the encoded ERBB2 fusion polypeptide comprises an ERBB2 kinase domain or a fragment of an ERBB2 kinase domain having ERBB2 kinase activity. In some embodiments, the encoded ERBB2 fusion polypeptide has ERBB2 kinase activity, optionally, the ERBB2 kinase activity is constitutive. In some embodiments, the encoded ERBB2 fusion polypeptide is oncogenic. In some embodiments, the encoded ERBB2 fusion polypeptide promotes cancer cell survival, angiogenesis, cancer cell proliferation, and any combination thereof. In some embodiments, the anti-cancer therapy is an ERBB2-targeted therapy. In some embodiments, the ERBB2 targeted therapy is a small molecule inhibitor, an antibody, a cell therapy, a nucleic acid, a viral-based therapy, an antibody-drug conjugate, a recombinant protein, a fusion protein, a natural compound, a peptide, a targeted proteolysis chimera (PROTAC), a treatment for an ERBB2-rearranged cancer, an ERBB2 targeted therapy being tested in a clinical trial, a treatment for an ERBB2-rearranged cancer being tested in a clinical trial, or any combination thereof. In some embodiments, the ERBB2 targeted therapy is a kinase inhibitor. In some embodiments, the ERBB2 targeted therapy is a tyrosine kinase inhibitor. In some embodiments, the ERBB2 targeted therapy is a multi-kinase inhibitor or an ERBB2-specific inhibitor. In some embodiments, the kinase inhibitor inhibits the kinase activity of an ERBB2 polypeptide.In some embodiments, the ERBB2 targeted therapy comprises one or more of afatinib, TAK-285, neratinib, dacomitinib, BMS-690514, BMS-599626, pelitinib, CP-724714, lapatinib, TAK-165, ARRY-380, AZD8931, AV-203, AMG-888, MM-111, MM-121, MM-141, LJM716, REGN1400, MEHD7945A, RG7116, trastuzumab, trastuzumab emtansine (T-DM1), pertuzumab, or APC 8024. In some embodiments, the nucleic acid inhibits expression of an ERBB2 fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule. In some embodiments, the nucleic acid is double-stranded RNA (dsRNA), small interfering RNA (siRNA), or small hairpin RNA (shRNA). In some embodiments, the cell therapy is adoptive therapy, T cell-based therapy, natural killer (NK) cell-based therapy, chimeric antigen receptor (CAR) T cell therapy, recombinant T cell receptor (TCR) T cell therapy, macrophage-based therapy, induced pluripotent stem cell-based therapy, B cell-based therapy, or dendritic cell (DC)-based therapy.

[0046] In some embodiments that may be combined with any of the above aspects or embodiments, the fusion nucleic acid molecule is an FGFR1 fusion nucleic acid molecule listed in any of Tables 1-6. In some embodiments, the FGFR1 fusion nucleic acid molecule encodes an FGFR1 fusion polypeptide. In some embodiments, the encoded FGFR1 fusion polypeptide comprises an FGFR1 kinase domain or a fragment of an FGFR1 kinase domain having FGFR1 kinase activity. In some embodiments, the encoded FGFR1 fusion polypeptide has FGFR1 kinase activity, optionally, the FGFR1 kinase activity is constitutive. In some embodiments, the encoded FGFR1 fusion polypeptide is oncogenic. In some embodiments, the encoded FGFR1 fusion polypeptide promotes cancer cell survival, angiogenesis, cancer cell proliferation, and any combination thereof. In some embodiments, the anti-cancer therapy is an FGFR1-targeted therapy. In some embodiments, the FGFR1 targeted therapy is a small molecule inhibitor, an antibody, a cell therapy, a nucleic acid, a virus-based therapy, an antibody-drug conjugate, a recombinant protein, a fusion protein, a natural compound, a peptide, a targeted proteolysis chimera (PROTAC), a treatment for an FGFR1-rearranged cancer, an FGFR1 targeted therapy being tested in a clinical trial, a treatment for an FGFR1-rearranged cancer being tested in a clinical trial, or any combination thereof. In some embodiments, the FGFR1 targeted therapy is a kinase inhibitor. In some embodiments, the FGFR1 targeted therapy is a tyrosine kinase inhibitor. In some embodiments, the FGFR1 targeted therapy is a multi-kinase inhibitor or an FGFR1-specific inhibitor. In some embodiments, the kinase inhibitor inhibits the kinase activity of an FGFR1 polypeptide.In some embodiments, the FGFR1 targeted therapy is selected from the group consisting of E3810 (lucitanib), AZD4547, dovitinib (TKI258), ponatinib, derazantinib (ARQ 087), nintendanib (BIBF1120), rogaratinib (BAY 1163877), 3D185, SOMCL-085, brivanib (BMS582664), lenvatinib (E7080), orantinib (TSU-68), PRN1371, XL-228, AZ12908010 (AZ8010), Devio-1347 (CH5183284), FIIN-2, LY2874455, infigratinib (BGJ398, NVP-BGJ398), pemigatinib, erdafitinib (JNJ-42756493), ASP5878, TAS-120, PRN1371, pazopanib, regorafenib, or PKC412. In some embodiments, the nucleic acid inhibits expression of an FGFR1 fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule. In some embodiments, the nucleic acid is double-stranded RNA (dsRNA), small interfering RNA (siRNA), or small hairpin RNA (shRNA). In some embodiments, the cell therapy is adoptive therapy, T cell-based therapy, natural killer (NK) cell-based therapy, chimeric antigen receptor (CAR) T cell therapy, recombinant T cell receptor (TCR) T cell therapy, macrophage-based therapy, induced pluripotent stem cell-based therapy, B cell-based therapy, or dendritic cell (DC)-based therapy.

[0047] In some embodiments that may be combined with any of the above aspects or embodiments, the fusion nucleic acid molecule is an FGFR2 fusion nucleic acid molecule listed in any of Tables 1-6. In some embodiments, the FGFR2 fusion nucleic acid molecule encodes an FGFR2 fusion polypeptide. In some embodiments, the encoded FGFR2 fusion polypeptide comprises an FGFR2 kinase domain or a fragment of an FGFR2 kinase domain having FGFR2 kinase activity. In some embodiments, the encoded FGFR2 fusion polypeptide has FGFR2 kinase activity, optionally, the FGFR2 kinase activity is constitutive. In some embodiments, the encoded FGFR2 fusion polypeptide is oncogenic. In some embodiments, the encoded FGFR2 fusion polypeptide promotes cancer cell survival, angiogenesis, cancer cell proliferation, and any combination thereof. In some embodiments, the method further comprises obtaining knowledge of or detecting the presence of an EGFR genetic mutation in a sample from the individual, optionally resulting in an L858R, L833V, and / or T790M amino acid substitution in the encoded EGFR polypeptide. In some embodiments, the individual has previously received treatment for cancer with erlotinib. In some embodiments, the fusion nucleic acid molecule and / or fusion polypeptide encoded by the fusion nucleic acid molecule confers resistance of the cancer to an EGFR-targeted anti-cancer therapy, optionally the EGFR-targeted anti-cancer therapy is a first-, second-, or third-generation EGFR tyrosine kinase inhibitor. In some embodiments, the fusion nucleic acid molecule and / or the encoded fusion polypeptide confers resistance to an EGFR-targeted anti-cancer therapy, optionally wherein the EGFR-targeted anti-cancer therapy is cetuximab, panitumumab, lapatinib, gefitinib, vandetanib, dacomitinib, icotinib, osimertinib (AZD9291), afatanib, olmutinib, EGF816 (nazartinib), avitinib (AC0010), rociletinib (CO-1686), BMS-690514, YH5448, PF-06747775, ASP8273, PF299804, AP26113, or erlotinib. In some embodiments, the anti-cancer therapy is an FGFR2-targeted therapy.In some embodiments, the FGFR2 targeted therapy is a small molecule inhibitor, an antibody, a cell therapy, a nucleic acid, a viral-based therapy, an antibody-drug conjugate, a recombinant protein, a fusion protein, a natural compound, a peptide, a targeted proteolysis chimera (PROTAC), a treatment for an FGFR2-rearranged cancer, an FGFR2 targeted therapy being tested in a clinical trial, a treatment for an FGFR2-rearranged cancer being tested in a clinical trial, or any combination thereof. In some embodiments, the FGFR2 targeted therapy is a kinase inhibitor. In some embodiments, the FGFR2 targeted therapy is a tyrosine kinase inhibitor. In some embodiments, the FGFR2 targeted therapy is a multi-kinase inhibitor or an FGFR2-specific inhibitor. In some embodiments, the kinase inhibitor inhibits the kinase activity of an FGFR2 polypeptide. In some embodiments, the FGFR2 targeted therapy is selected from the group consisting of E3810 (lucitanib), AZD4547, dovitinib (TKI258), ponatinib, derazantinib (ARQ 087), nintendanib (BIBF1120), rogaratinib (BAY 1163877), 3D185, SOMCL-085, brivanib (BMS582664), lenvatinib (E7080), orantinib (TSU-68), PRN1371, XL-228, AZ12908010 (AZ8010), Debio-1347 (CH5183284), FIIN-2, LY2874455, IgE ... The nucleic acid may comprise one or more of ampligratinib (BGJ398, NVP-BGJ398), pemigatinib, erdafitinib, ASP5878, TAS-120, PRN1371, formononetin, RO4383596, Ki23057, SU5402, RLY-4008, pazopanib, regorafenib, or PKC412. In some embodiments, the nucleic acid inhibits expression of an FGFR2 fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule. In some embodiments, the nucleic acid is double-stranded RNA (dsRNA), small interfering RNA (siRNA), or short hairpin RNA (shRNA).In some embodiments, the cell therapy is adoptive therapy, T cell-based therapy, natural killer (NK) cell-based therapy, chimeric antigen receptor (CAR) T cell therapy, recombinant T cell receptor (TCR) T cell therapy, macrophage-based therapy, induced pluripotent stem cell-based therapy, B cell-based therapy, or dendritic cell (DC)-based therapy.

[0048] In some embodiments that may be combined with any of the above aspects or embodiments, the fusion nucleic acid molecule is an FGFR3 fusion nucleic acid molecule listed in any of Tables 1-6. In some embodiments, the FGFR3 fusion nucleic acid molecule encodes an FGFR3 fusion polypeptide. In some embodiments, the encoded FGFR3 fusion polypeptide comprises an FGFR3 kinase domain or a fragment of an FGFR3 kinase domain having FGFR3 kinase activity. In some embodiments, the encoded FGFR3 fusion polypeptide has FGFR3 kinase activity, optionally, the FGFR3 kinase activity is constitutive. In some embodiments, the encoded FGFR3 fusion polypeptide is oncogenic. In some embodiments, the encoded FGFR3 fusion polypeptide promotes cancer cell survival, angiogenesis, cancer cell proliferation, and any combination thereof. In some embodiments, the method includes detecting in a sample from the individual: (a) a mutation in the EGFR gene, optionally a deletion of exon 19 or a portion thereof of EGFR, an EGFR gene amplification, or a mutation resulting in a T790M, C797G, V441G, G465R, E709K, or L858R amino acid substitution in the encoded EGFR polypeptide, or any combination thereof; (b) a mutation in the BRAF gene, optionally resulting in a V600E amino acid substitution in the encoded BRAF polypeptide; (c) a wild-type KRAS gene or a mutation in the KRAS gene, optionally resulting in a Q61H amino acid substitution in the encoded KRAS polypeptide; (d) a mutation in the ESR1 gene, optionally resulting in a Y537N and / or a D538G amino acid substitution in the encoded ESR1 polypeptide; (e) a mutation in the AKT1 gene, optionally resulting in an E17K amino acid substitution in the encoded AKT1 polypeptide; or further comprising obtaining knowledge of or detecting the presence of any combination of (a)-(e).In some embodiments, the method comprises detecting in a sample from the individual: (a) a mutation in the EGFR gene, optionally a deletion of exon 19 or a portion thereof of EGFR, an EGFR gene amplification, or a mutation resulting in a S492R, V441G, G465R, E709K, or L858R amino acid substitution in the encoded EGFR polypeptide, or any combination thereof; (b) a wild-type KRAS gene, or a mutation in the KRAS gene, optionally resulting in a G12C, G13D, and / or Q61H amino acid substitution in the encoded KRAS polypeptide; (c) a mutation in the ESR1 gene, optionally resulting in a Y537N and / or D538G amino acid substitution in the encoded ESR1 polypeptide; (d) a mutation in the AKT1 gene, optionally resulting in a E17K or E17K amino acid substitution in the encoded AKT1 polypeptide. (e) a mutation in the BRAF gene, optionally resulting in a V600E amino acid substitution in the encoded BRAF polypeptide; (f) a mutation in the HRAS gene, optionally resulting in a Q61L amino acid substitution in the encoded HRAS polypeptide; (g) a mutation in the MAP2K1 gene, optionally resulting in an E102_I103del mutation and / or a K57T amino acid substitution in the encoded MAP2K1 polypeptide; (h) a mutation in the NRAS gene, optionally resulting in a Q61K amino acid substitution in the encoded NRAS polypeptide; or any combination of (a)-(h), wherein the FGFR3 fusion nucleic acid molecule is an FGFR3-TACC3 fusion nucleic acid molecule listed in Table 2 or 6. In some embodiments, the cancer is colorectal cancer, non-small cell lung cancer, or breast cancer. In some embodiments, the sample comprises a deletion of exon 19 or a portion thereof of EGFR. In some embodiments, the sample contains an EGFR gene mutation that results in a L858R and / or an E709K amino acid substitution in the encoded EGFR polypeptide.In some embodiments, the individual has previously received cancer treatment with afatinib and / or cetuximab. In some embodiments, the individual has experienced stable disease during or after treatment with afatinib and / or cetuximab. In some embodiments, the method further includes obtaining knowledge of or detecting the presence of, in a sample from the individual, a mutation in the BRAF gene resulting in a V600E amino acid substitution in the encoded BRAF polypeptide; a mutation in the EGFR gene resulting in a S492R and / or V441G amino acid substitution in the encoded EGFR polypeptide; a wild-type KRAS gene; a mutation in the HRAS gene resulting in a Q61L amino acid substitution in the encoded HRAS polypeptide; a mutation in the MAP2K1 gene resulting in an E102_I103del mutation and / or a K57T amino acid substitution in the encoded MAP2K1 polypeptide; and a mutation in the NRAS gene resulting in a Q61K amino acid substitution in the encoded NRAS polypeptide, wherein the FGFR3 fusion nucleic acid molecule is an FGFR3-TACC3 fusion nucleic acid molecule listed in Table 2 or 6. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer has been previously treated with 5-FU; a combination of folinic acid, 5-FU, and irinotecan (FOLFIRI) with bevacizumab; a combination of FOLFIRI and cetuximab; a combination of folinic acid, 5-FU, and oxaliplatin (FOLFOX) with bevacizumab; and / or a combination of pembrolizumab and regorafenib. In some embodiments, the method further includes obtaining knowledge of or detecting the presence of a mutation in the KRAS gene resulting in a G12C and / or G13D amino acid substitution in the encoded KRAS polypeptide; a mutation in the MAP2K1 gene resulting in an E102_I103del mutation in the encoded MAP2K1 polypeptide; and a mutation in the NRAS gene resulting in a Q61K amino acid substitution in the encoded NRAS polypeptide in a sample from the individual, wherein the FGFR3 fusion nucleic acid molecule is an FGFR3-TACC3 fusion nucleic acid molecule listed in Table 2 or 6. In some embodiments, the cancer is colorectal cancer.In some embodiments, the cancer has been previously treated with adagrasib or a combination of adagrasib and cetuximab. In some embodiments, the sample comprises EGFR gene amplification, an EGFR gene mutation resulting in a V441G and / or G465R amino acid substitution in the encoded EGFR polypeptide, and a KRAS gene mutation resulting in a Q61H amino acid substitution in the encoded KRAS polypeptide, and the cancer is colorectal cancer. In some embodiments, the sample comprises EGFR gene amplification, an EGFR gene mutation resulting in a V441G and / or G465R amino acid substitution in the encoded EGFR polypeptide, and a wild-type KRAS gene, and the cancer is colorectal cancer. In some embodiments, the individual has previously received cancer treatment with FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan), bevacizumab, and / or panitumumab. In some embodiments, the method further comprises obtaining knowledge of or detecting the presence of a SNRNP70-MET gene fusion in a sample from the individual. In some embodiments, the sample comprises an ESR1 gene mutation resulting in a Y537N and / or D538G amino acid substitution in the encoded ESR1 polypeptide and an AKT1 gene mutation resulting in an E17K amino acid substitution in the encoded AKT1 polypeptide, and the cancer is breast cancer. In some embodiments, the cancer is estrogen receptor positive (ER+) and / or progesterone receptor positive (PR+). In some embodiments, the cancer has previously been treated with everolimus, denosumab, and / or fulvestrant. In some embodiments, the fusion nucleic acid molecule and / or the fusion polypeptide encoded by the fusion nucleic acid molecule confers resistance of the cancer to hormonal anticancer therapy.In some embodiments, the method further comprises obtaining knowledge of or detecting the presence of (a) a mutation in the EGFR gene, optionally resulting in a deletion of exon 19 or a portion thereof of EGFR, or a mutation resulting in a T790M and / or a C797G amino acid substitution in the encoded EGFR polypeptide, or any combination thereof; (b) a mutation in the BRAF gene, optionally resulting in a V600E amino acid substitution in the encoded BRAF polypeptide; or both (a) and (b), in a sample from the individual, wherein the FGFR3 fusion nucleic acid molecule is an FGFR3-ADD1 fusion nucleic acid molecule listed in Table 2 or 6. In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the sample comprises an EGFR gene mutation resulting in a deletion of exon 19 or a portion thereof of EGFR, a T790M and / or a C797G amino acid substitution in the encoded EGFR polypeptide, and a BRAF gene mutation resulting in a V600E amino acid substitution in the encoded BRAF polypeptide. In some embodiments, the individual has previously received treatment for cancer with osimertinib. In some embodiments, the individual experiences stable disease during or after treatment with osimertinib. In some embodiments, the fusion nucleic acid molecule and / or the fusion polypeptide encoded by the fusion nucleic acid molecule confers resistance to an EGFR-targeted anti-cancer therapy, optionally, the EGFR-targeted anti-cancer therapy is a first-, second-, or third-generation EGFR tyrosine kinase inhibitor. In some embodiments, the fusion nucleic acid molecule and / or the fusion polypeptide encoded by the fusion nucleic acid molecule confers resistance of a cancer to an EGFR-targeted anti-cancer therapy, optionally wherein the EGFR-targeted anti-cancer therapy is cetuximab, panitumumab, lapatinib, gefitinib, vandetanib, dacomitinib, icotinib, osimertinib (AZD9291), afatanib, olmutinib, EGF816 (nazartinib), avitinib (AC0010), rociletinib (CO-1686), BMS-690514, YH5448, PF-06747775, ASP8273, PF299804, AP26113, or erlotinib.In some embodiments, the anti-cancer therapy is an FGFR3 targeted therapy. In some embodiments, the FGFR3 targeted therapy is a small molecule inhibitor, an antibody, a cell therapy, a nucleic acid, a virus-based therapy, an antibody-drug conjugate, a recombinant protein, a fusion protein, a natural compound, a peptide, a targeted proteolysis chimera (PROTAC), a treatment for an FGFR3-rearranged cancer, an FGFR3 targeted therapy being tested in a clinical trial, a treatment for an FGFR3-rearranged cancer being tested in a clinical trial, or any combination thereof. In some embodiments, the FGFR3 targeted therapy is a kinase inhibitor. In some embodiments, the FGFR3 targeted therapy is a tyrosine kinase inhibitor. In some embodiments, the FGFR3 targeted therapy is a multi-kinase inhibitor or an FGFR3-specific inhibitor. In some embodiments, the kinase inhibitor inhibits the kinase activity of an FGFR3 polypeptide. In some embodiments, the FGFR3 targeted therapy is E3810 (lucitanib). AZD4547, dovitinib (TKI258), ponatinib, derazantinib (ARQ 087), nintendanib (BIBF1120), rogaratinib (BAY 1163877), 3D185, SOMCL-085, brivanib (BMS582664), lenvatinib (E7080), orantinib (TSU-68), PRN1371, XL-228, AZ12908010 (AZ8010), Devio-1347 (CH5183284), FIIN-2, LY2874455, infigratinib (BGJ398, NVP-BGJ398), pemigatinib, erdafitinib, ASP5878, TAS-120, PRN1371, PKC412, bofatamab (B-70), pazopanib, or MFGR1877S. In some embodiments, the nucleic acid inhibits expression of an FGFR3 fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule. In some embodiments, the nucleic acid is double-stranded RNA (dsRNA), small interfering RNA (siRNA), or small hairpin RNA (shRNA). In some embodiments, the cell therapy is adoptive therapy, T cell-based therapy, natural killer (NK) cell-based therapy, chimeric antigen receptor (CAR) T cell therapy, recombinant T cell receptor (TCR) T cell therapy, macrophage-based therapy, induced pluripotent stem cell-based therapy, B cell-based therapy, or dendritic cell (DC)-based therapy.

[0049] In some embodiments that may be combined with any of the above aspects or embodiments, the fusion nucleic acid molecule is a MET fusion nucleic acid molecule listed in any of Tables 1-6. In some embodiments, the MET fusion nucleic acid molecule encodes a MET fusion polypeptide. In some embodiments, the encoded MET fusion polypeptide comprises a MET kinase domain or a fragment of a MET kinase domain that has MET kinase activity. In some embodiments, the encoded MET fusion polypeptide has MET kinase activity, optionally, the MET kinase activity is constitutive. In some embodiments, the encoded MET fusion polypeptide is oncogenic. In some embodiments, the encoded MET fusion polypeptide promotes cancer cell survival, angiogenesis, cancer cell proliferation, and any combination thereof. In some embodiments, the method further comprises obtaining knowledge of or detecting the presence, in a sample from the individual, of: (a) a mutation in the EGFR gene, optionally an EGFR gene amplification, or a mutation resulting in a V441G and / or a G465R amino acid substitution in the encoded EGFR polypeptide, or any combination thereof; and / or (b) a wild-type KRAS gene, or a mutation in the KRAS gene, optionally resulting in a Q61H amino acid substitution in the encoded KRAS polypeptide. In some embodiments, the method further comprises obtaining knowledge of or detecting the presence, in a sample from the individual, of: EGFR gene amplification; an EGFR gene mutation resulting in a V441G and / or a G465R amino acid substitution in the encoded EGFR polypeptide; and a wild-type KRAS gene or a KRAS gene mutation resulting in a Q61H amino acid substitution in the encoded KRAS polypeptide, wherein the MET fusion nucleic acid molecule is a MET-SNRNP70 fusion nucleic acid molecule listed in any of Tables 1 and 3-5. In some embodiments, the method further comprises obtaining knowledge of or detecting the presence of an FGFR3-TACC3 gene fusion in a sample from the individual.In some embodiments, the individual has previously received treatment for cancer with FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan), bevacizumab, and / or panitumumab. In some embodiments, the method further includes obtaining knowledge of or detecting the presence of, in a sample from the individual: EGFR gene amplification; and a wild-type KRAS gene or a KRAS gene mutation resulting in a Q61H amino acid substitution in the encoded KRAS polypeptide, wherein the MET fusion nucleic acid molecule is a MET-CAPZA2 fusion nucleic acid molecule listed in Table 2 or 6. In some embodiments, the cancer is colorectal cancer. In some embodiments, the fusion nucleic acid molecule and / or the fusion polypeptide encoded by the fusion nucleic acid molecule confers resistance of the cancer to an EGFR-targeted anticancer therapy, and optionally, the EGFR-targeted anticancer therapy is a first-, second-, or third-generation EGFR tyrosine kinase inhibitor. In some embodiments, the fusion nucleic acid molecule and / or the fusion polypeptide encoded by the fusion nucleic acid molecule confers resistance of a cancer to an EGFR-targeted anti-cancer therapy, optionally wherein the EGFR-targeted anti-cancer therapy is cetuximab, panitumumab, lapatinib, gefitinib, vandetanib, dacomitinib, icotinib, osimertinib (AZD9291), afatanib, olmutinib, EGF816 (nazartinib), avitinib (AC0010), rociletinib (CO-1686), BMS-690514, YH5448, PF-06747775, ASP8273, PF299804, AP26113, or erlotinib. In some embodiments, the anti-cancer therapy is a MET-targeted therapy. In some embodiments, the MET-targeted therapy is a small molecule inhibitor, an antibody, a cell therapy, a nucleic acid, a viral-based therapy, an antibody-drug conjugate, a recombinant protein, a fusion protein, a natural compound, a peptide, a targeted proteolysis chimera (PROTAC), a treatment for a MET-rearranged cancer, a MET-targeted therapy being tested in a clinical trial, a treatment for a MET-rearranged cancer being tested in a clinical trial, or any combination thereof. In some embodiments, the MET-targeted therapy is a kinase inhibitor. In some embodiments, the MET-targeted therapy is a tyrosine kinase inhibitor.In some embodiments, the MET-targeted therapy is a multikinase inhibitor or a MET-specific inhibitor. In some embodiments, the kinase inhibitor inhibits the kinase activity of a MET polypeptide. In some embodiments, the MET-targeted therapy comprises PHA-665752, crizotinib, cabozantinib, or capmatinib (INC280). In some embodiments, the nucleic acid inhibits expression of a MET fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule. In some embodiments, the nucleic acid is double-stranded RNA (dsRNA), small interfering RNA (siRNA), or short hairpin RNA (shRNA). In some embodiments, the cell therapy is adoptive therapy, T cell-based therapy, natural killer (NK) cell-based therapy, chimeric antigen receptor (CAR) T cell therapy, recombinant T cell receptor (TCR) T cell therapy, macrophage-based therapy, induced pluripotent stem cell-based therapy, B cell-based therapy, or dendritic cell (DC)-based therapy.

[0050] In some embodiments that may be combined with any of the above aspects or embodiments, the fusion nucleic acid molecule is a RAF1 fusion nucleic acid molecule listed in any of Tables 1-6. In some embodiments, the RAF1 fusion nucleic acid molecule encodes a RAF1 fusion polypeptide. In some embodiments, the encoded RAF1 fusion polypeptide comprises a RAF1 kinase domain or a fragment of a RAF1 kinase domain that has RAF1 kinase activity. In some embodiments, the encoded RAF1 fusion polypeptide has RAF1 kinase activity, and optionally, the RAF1 kinase activity is constitutive. In some embodiments, the encoded RAF1 fusion polypeptide is oncogenic. In some embodiments, the encoded RAF1 fusion polypeptide promotes cancer cell survival, angiogenesis, cancer cell proliferation, and any combination thereof. In some embodiments, the method comprises detecting in a sample from the individual: (a) a mutation in the BRAF gene, optionally resulting in a V600E amino acid substitution in the encoded BRAF polypeptide; (b) a mutation in the EGFR gene, optionally resulting in a S492R and / or a V441G amino acid substitution in the encoded EGFR polypeptide; (c) a wild-type KRAS gene, or a mutation in the KRAS gene, optionally resulting in a G12C and / or G13D amino acid substitution in the encoded KRAS polypeptide; (d) a mutation in the HRAS gene, optionally resulting in a Q61L amino acid substitution in the encoded HRAS polypeptide; (e) a mutation in the MAP2K1 gene, optionally resulting in an E102_I103del mutation and / or a K57T amino acid substitution in the encoded MAP2K1 polypeptide; and / or (f) a mutation in the NRAS gene, optionally resulting in a Q61K amino acid substitution in the encoded NRAS polypeptide.In some embodiments, the method further comprises obtaining knowledge of or detecting the presence, in a sample from the individual, of a mutation in the BRAF gene resulting in a V600E amino acid substitution in the encoded BRAF polypeptide; a mutation in the EGFR gene resulting in a S492R and / or V441G amino acid substitution in the encoded EGFR polypeptide; a wild-type KRAS gene; a mutation in the HRAS gene resulting in a Q61L amino acid substitution in the encoded HRAS polypeptide; a mutation in the MAP2K1 gene resulting in an E102_I103del mutation and / or a K57T amino acid substitution in the encoded MAP2K1 polypeptide; and a mutation in the NRAS gene resulting in a Q61K amino acid substitution in the encoded NRAS polypeptide, wherein the RAF1 fusion nucleic acid molecule is a RAF1-SYN2 fusion nucleic acid molecule listed in any of Tables 1 and 3-5. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer has been previously treated with 5-FU; a combination of folinic acid, 5-FU, and irinotecan (FOLFIRI) with bevacizumab; a combination of FOLFIRI with cetuximab; a combination of folinic acid, 5-FU, and oxaliplatin (FOLFOX) with bevacizumab; and / or a combination of pembrolizumab with regorafenib. In some embodiments, the method further comprises obtaining knowledge of or detecting the presence of, in a sample from the individual, a mutation in the KRAS gene resulting in a G12C and / or G13D amino acid substitution in the encoded KRAS polypeptide; a mutation in the MAP2K1 gene resulting in an E102_I103del mutation in the encoded MAP2K1 polypeptide; and a mutation in the NRAS gene resulting in a Q61K amino acid substitution in the encoded NRAS polypeptide, wherein the RAF1 fusion nucleic acid molecule is a RAF1-TRAK1 fusion nucleic acid molecule listed in Table 2 or 6. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer has been previously treated with adagrasib or a combination of adagrasib and cetuximab, hi some embodiments, the anti-cancer therapy is a RAF1 targeted therapy.In some embodiments, the RAF1 targeted therapy is a small molecule inhibitor, an antibody, a cell therapy, a nucleic acid, a virus-based therapy, an antibody-drug conjugate, a recombinant protein, a fusion protein, a natural compound, a peptide, a targeted proteolysis chimera (PROTAC), a treatment for a RAF1-rearranged cancer, a RAF1 targeted therapy being tested in a clinical trial, a treatment for a RAF1-rearranged cancer being tested in a clinical trial, or any combination thereof. In some embodiments, the RAF1 targeted therapy is a kinase inhibitor. In some embodiments, the RAF1 targeted therapy is a serine / threonine kinase inhibitor. In some embodiments, the RAF1 targeted therapy is a multi-kinase inhibitor or a RAF1-specific inhibitor. In some embodiments, the kinase inhibitor inhibits the kinase activity of a RAF1 polypeptide. In some embodiments, the RAF1 targeted therapy comprises one or more of sorafenib (BAY49-9006), binimetinib, cobimetinib, regorafenib, trametinib, or RAF265. In some embodiments, the nucleic acid inhibits expression of a RAF1 fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule. In some embodiments, the nucleic acid is double-stranded RNA (dsRNA), small interfering RNA (siRNA), or small hairpin RNA (shRNA). In some embodiments, the cell therapy is adoptive therapy, T cell-based therapy, natural killer (NK) cell-based therapy, chimeric antigen receptor (CAR) T cell therapy, recombinant T cell receptor (TCR) T cell therapy, macrophage-based therapy, induced pluripotent stem cell-based therapy, B cell-based therapy, or dendritic cell (DC)-based therapy.

[0051] In some embodiments that may be combined with any of the above aspects or embodiments, the fusion nucleic acid molecule is a RET fusion nucleic acid molecule listed in any of Tables 1-6. In some embodiments, the RET fusion nucleic acid molecule encodes a RET fusion polypeptide. In some embodiments, the encoded RET fusion polypeptide comprises a RET kinase domain or a fragment of a RET kinase domain having RET kinase activity. In some embodiments, the encoded RET fusion polypeptide has RET kinase activity, optionally, the RET kinase activity is constitutive. In some embodiments, the encoded RET fusion polypeptide is oncogenic. In some embodiments, the encoded RET fusion polypeptide promotes cancer cell survival, angiogenesis, cancer cell proliferation, and any combination thereof. In some embodiments, the method further comprises obtaining knowledge of or detecting the presence of, in a sample from the individual: (a) a mutation in the EGFR gene, optionally resulting in a deletion of exon 19 or a portion thereof of EGFR, or a mutation resulting in a T790M amino acid substitution in the encoded EGFR polypeptide, or both; (b) a mutation in the PIK3CA gene, optionally resulting in an E542K amino acid substitution in the encoded PIK3CA polypeptide; (c) a mutation in the KRAS gene, optionally resulting in a G12C amino acid substitution in the encoded KRAS polypeptide; (d) a mutation in the ESR1 gene, optionally resulting in an E380Q amino acid substitution in the encoded ESR1 polypeptide; or (e) a mutation in the PTEN gene, optionally resulting in an S59* and / or M1341 amino acid substitution in the encoded PTEN polypeptide; or any combination of (a)-(e). In some embodiments, the method further comprises obtaining knowledge of or detecting the presence of a deletion of exon 19 or a portion thereof of EGFR in a sample from the individual, wherein the RET fusion nucleic acid molecule is a RET-ERC1 fusion nucleic acid molecule listed in Table 2 or 6.In some embodiments, the method further comprises obtaining knowledge of or detecting the presence of an EGFR genetic mutation resulting in a deletion of exon 19 or a portion thereof of EGFR and a T790M amino acid substitution in the encoded EGFR polypeptide, wherein the RET fusion nucleic acid molecule is a RET-NCOA4 fusion nucleic acid molecule listed in Table 2 or 6. In some embodiments, the individual has been previously treated with osimertinib. In some embodiments, the fusion nucleic acid molecule and / or the fusion polypeptide encoded by the fusion nucleic acid molecule confers resistance of the cancer to an EGFR-targeted anti-cancer therapy, optionally the EGFR-targeted anti-cancer therapy is a first-, second-, or third-generation EGFR tyrosine kinase inhibitor. In some embodiments, the fusion nucleic acid molecule and / or the fusion polypeptide encoded by the fusion nucleic acid molecule confers resistance of a cancer to an EGFR-targeted anti-cancer therapy, optionally wherein the EGFR-targeted anti-cancer therapy is cetuximab, panitumumab, lapatinib, gefitinib, vandetanib, dacomitinib, icotinib, osimertinib (AZD9291), afatanib, olmutinib, EGF816 (nazartinib), avitinib (AC0010), rociletinib (CO-1686), BMS-690514, YH5448, PF-06747775, ASP8273, PF299804, AP26113, or erlotinib. In some embodiments, the method further comprises obtaining knowledge of or detecting the presence, in a sample from the individual, of a PIK3CA genetic mutation resulting in an E542K amino acid substitution in the encoded PIK3CA polypeptide; an ESR1 genetic mutation resulting in an E380Q amino acid substitution in the encoded ESR1 polypeptide; a KRAS genetic mutation resulting in a G12C amino acid substitution in the encoded KRAS polypeptide; and a PTEN genetic mutation resulting in a S59* and / or M134I amino acid substitution in the encoded PTEN polypeptide, wherein the RET fusion nucleic acid molecule is a RET-BAIAP2L1 fusion nucleic acid molecule listed in any of Tables 1 and 3-5. In some embodiments, the cancer is breast cancer.In some embodiments, the fusion nucleic acid molecule and / or the fusion polypeptide encoded by the fusion nucleic acid molecule confers resistance of the cancer to PI3K-targeted therapy. In some embodiments, the method further includes obtaining knowledge of or detecting the presence of an EGFR genetic mutation resulting in a T790M and / or L858R amino acid substitution in the encoded EGFR polypeptide in a sample from the individual, wherein the RET fusion nucleic acid molecule is a RET-CCDC6 fusion nucleic acid molecule listed in Table 2 or 6. In some embodiments, the anti-cancer therapy is a RET-targeted therapy. In some embodiments, the RET-targeted therapy is a small molecule inhibitor, an antibody, a cell therapy, a nucleic acid, a virus-based therapy, an antibody-drug conjugate, a recombinant protein, a fusion protein, a natural compound, a peptide, a targeted proteolysis chimera (PROTAC), a treatment for a RET-rearranged cancer, a RET-targeted therapy being tested in a clinical trial, a treatment for a RET-rearranged cancer being tested in a clinical trial, or any combination thereof. In some embodiments, the RET-targeted therapy is a kinase inhibitor. In some embodiments, the RET-targeted therapy is a tyrosine kinase inhibitor. In some embodiments, the RET targeted therapy is a multikinase inhibitor or a RET-specific inhibitor. In some embodiments, the kinase inhibitor inhibits the kinase activity of the RET polypeptide. In some embodiments, the RET targeted therapy comprises one or more of selpercatinib, pralsetinib, alectinib, cabozantinib, lenvatinib, ponatinib, regorafenib, sorafenib, sunitinib, or vandetanib. In some embodiments, the nucleic acid inhibits the expression of a RET fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule. In some embodiments, the nucleic acid is double-stranded RNA (dsRNA), small interfering RNA (siRNA), or short hairpin RNA (shRNA). In some embodiments, the cell therapy is adoptive therapy, T cell-based therapy, natural killer (NK) cell-based therapy, chimeric antigen receptor (CAR) T cell therapy, recombinant T cell receptor (TCR) T cell therapy, macrophage-based therapy, induced pluripotent stem cell-based therapy, B cell-based therapy, or dendritic cell (DC)-based therapy.

[0052] In some embodiments that may be combined with any of the above aspects or embodiments, the fusion nucleic acid molecule is a ROS1 fusion nucleic acid molecule listed in any of Tables 1-6. In some embodiments, the ROS1 fusion nucleic acid molecule encodes a ROS1 fusion polypeptide. In some embodiments, the encoded ROS1 fusion polypeptide comprises a ROS1 kinase domain or a fragment of a ROS1 kinase domain having ROS1 kinase activity. In some embodiments, the encoded ROS1 fusion polypeptide has ROS1 kinase activity, optionally, the ROS1 kinase activity is constitutive. In some embodiments, the encoded ROS1 fusion polypeptide is oncogenic. In some embodiments, the encoded ROS1 fusion polypeptide promotes cancer cell survival, angiogenesis, cancer cell proliferation, and any combination thereof. In some embodiments, the method further comprises obtaining knowledge of or detecting the presence of a PIK3CA gene mutation in a sample from the individual, optionally resulting in an E545K amino acid substitution in the encoded PIK3CA polypeptide. In some embodiments, the ROS1 fusion nucleic acid molecule is a ROS1-GOPC fusion nucleic acid molecule listed in Table 2 or 6, and the sample contains a PIK3CA gene mutation resulting in an E545K amino acid substitution in the encoded PIK3CA polypeptide. In some embodiments, the fusion nucleic acid molecule and / or the fusion polypeptide encoded by the fusion nucleic acid molecule confers cancer resistance to PI3K-targeted therapy. In some embodiments, the anti-cancer therapy is a ROS1-targeted therapy. In some embodiments, the ROS1-targeted therapy is a small molecule inhibitor, an antibody, a cell therapy, a nucleic acid, a virus-based therapy, an antibody-drug conjugate, a recombinant protein, a fusion protein, a natural compound, a peptide, a targeted proteolysis chimera (PROTAC), a treatment for a ROS1-rearranged cancer, a ROS1-targeted therapy being tested in a clinical trial, a treatment for a ROS1-rearranged cancer being tested in a clinical trial, or any combination thereof. In some embodiments, the ROS1-targeted therapy is a kinase inhibitor. In some embodiments, the ROS1-targeted therapy is a tyrosine kinase inhibitor.In some embodiments, the ROS1-targeted therapy is a multikinase inhibitor or a ROS1-specific inhibitor. In some embodiments, the kinase inhibitor inhibits the kinase activity of the ROS1 polypeptide. In some embodiments, the ROS1-targeted therapy comprises one or more of crizotinib, lorlatinib, TQ-B3139, repotrectinib (TPX-0005), brigutinib, cabozantinib, ceritinib, or entrectinib. In some embodiments, the nucleic acid inhibits expression of a ROS1 fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule. In some embodiments, the nucleic acid is double-stranded RNA (dsRNA), small interfering RNA (siRNA), or short hairpin RNA (shRNA). In some embodiments, the cell therapy is adoptive therapy, T cell-based therapy, natural killer (NK) cell-based therapy, chimeric antigen receptor (CAR) T cell therapy, recombinant T cell receptor (TCR) T cell therapy, macrophage-based therapy, induced pluripotent stem cell-based therapy, B cell-based therapy, or dendritic cell (DC)-based therapy.

[0053] In some embodiments that may be combined with any of the above aspects or embodiments, the fusion nucleic acid molecule is an NTRK1 fusion nucleic acid molecule listed in any of Tables 2 and 6. In some embodiments, the NTRK1 fusion nucleic acid molecule encodes an NTRK1 fusion polypeptide. In some embodiments, the encoded NTRK1 fusion polypeptide comprises an NTRK1 kinase domain or a fragment of the NTRK1 kinase domain that has NTRK1 kinase activity. In some embodiments, the encoded NTRK1 fusion polypeptide has NTRK1 kinase activity, and optionally, the NTRK1 kinase activity is constitutive. In some embodiments, the encoded NTRK1 fusion polypeptide is oncogenic. In some embodiments, the encoded NTRK1 fusion polypeptide promotes cancer cell survival, angiogenesis, cancer cell proliferation, and any combination thereof. In some embodiments, the anti-cancer therapy is an NTRK1-targeted therapy. In some embodiments, the NTRK1 targeted therapy is a small molecule inhibitor, an antibody, a cell therapy, a nucleic acid, a virus-based therapy, an antibody-drug conjugate, a recombinant protein, a fusion protein, a natural compound, a peptide, a targeted proteolysis chimera (PROTAC), a treatment for an NTRK1-rearranged cancer, an NTRK1 targeted therapy being tested in a clinical trial, a treatment for an NTRK1-rearranged cancer being tested in a clinical trial, or any combination thereof. In some embodiments, the NTRK1 targeted therapy is a kinase inhibitor. In some embodiments, the NTRK1 targeted therapy is a tyrosine kinase inhibitor. In some embodiments, the NTRK1 targeted therapy is a multi-kinase inhibitor or an NTRK1-specific inhibitor. In some embodiments, the kinase inhibitor inhibits the kinase activity of an NTRK1 polypeptide.In some embodiments, the NTRK1 targeted therapy is selected from the group consisting of altiratinib (DCC-2701), AG 879 (tyrphostin AG 879), anti-TrK antibodies, ARRY 954, AR523, AZ-23, AZ623, benzotriazoles, CEP-2563, danusertib (PHA-739358), entrectinib, DS-6051, GNF 5837, GW 441756, indenopyrrolocarbazole 12a, isothiazole 5n, larotrectinib, lestaurtinib (CEP-701), ceritrectinib (LOXO-195), macrocycle, ONO-5390556, oxindole 3, pegcantratinib (SNA-120), PHA-848125, PLX7486, pyrazole derivative, pyrazolo[1;5a]pyrimidine, pyridocarbazole, pyridoquinazolinyl, pyridotriazole, pyrrolidinylthiourea, pyrrolidinylurea, pyrrolo[2;3-d]pyrimidine, quinazolinyl, repotrectinib (TPX-0005), Ro In some embodiments, the nucleic acid inhibits expression of an NTRK1 fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule. In some embodiments, the nucleic acid is a double-stranded RNA (dsRNA), a small interfering RNA (siRNA), or a small hairpin RNA (shRNA). In some embodiments, the cell therapy is adoptive therapy, T cell-based therapy, natural killer (NK) cell-based therapy, chimeric antigen receptor (CAR) T cell therapy, recombinant T cell receptor (TCR) T cell therapy, macrophage-based therapy, induced pluripotent stem cell-based therapy, B cell-based therapy, or dendritic cell (DC)-based therapy.

[0054] In some embodiments that may be combined with any of the above aspects or embodiments, the treatment or one or more treatment options further comprise an additional anti-cancer therapy. In some embodiments, the additional anti-cancer therapy comprises one or more of a small molecule inhibitor, a chemotherapeutic agent, a cancer immunotherapy, an antibody, a cell therapy, a nucleic acid, surgery, radiation therapy, an anti-angiogenic therapy, an anti-DNA repair therapy, an anti-inflammatory therapy, an anti-tumor agent, a growth inhibitory agent, a cytotoxic agent, a vaccine, a small molecule agonist, a virus-based therapy, an antibody-drug conjugate, a recombinant protein, a fusion protein, a natural compound, a peptide, a targeted proteolytic chimera (PROTAC), or any combination thereof. In some embodiments, the cell therapy is adoptive therapy, T cell-based therapy, natural killer (NK) cell-based therapy, chimeric antigen receptor (CAR) T cell therapy, recombinant T cell receptor (TCR) T cell therapy, macrophage-based therapy, induced pluripotent stem cell-based therapy, B cell-based therapy, or dendritic cell (DC)-based therapy. In some embodiments, the nucleic acid comprises double-stranded RNA (dsRNA), small interfering RNA (siRNA), or small hairpin RNA (shRNA).

[0055] In some embodiments that may be combined with any of the above aspects or embodiments, the method further comprises obtaining a sample from the individual. In some embodiments that may be combined with any of the above aspects or embodiments, the sample is obtained from a cancer. In some embodiments that may be combined with any of the above aspects or embodiments, the sample comprises a tissue biopsy sample, a liquid biopsy sample, or a normal control. In some embodiments, the sample is from a tumor biopsy, a tumor specimen, or circulating tumor cells. In some embodiments, the sample is a liquid biopsy sample and comprises blood, plasma, cerebrospinal fluid, sputum, stool, urine, or saliva. In some embodiments, the sample comprises cells and / or nucleic acids from the cancer. In some embodiments, the sample comprises mRNA, DNA, circulating tumor DNA (ctDNA), cell-free DNA, or cell-free RNA from the cancer. In some embodiments, the sample is a liquid biopsy sample and comprises circulating tumor cells (CTCs). In some embodiments, the sample is a liquid biopsy sample and comprises cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), or any combination thereof.

[0056] In some embodiments that may be combined with any of the above aspects or embodiments, the method includes obtaining knowledge of or detecting a fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule in a tissue biopsy sample, a liquid biopsy sample, or both a tissue biopsy sample and a liquid biopsy sample from the individual.

[0057] In some embodiments that may be combined with any of the above aspects or embodiments, obtaining knowledge comprises detecting, in the sample, the fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule.

[0058] In some embodiments that may be combined with any of the preceding aspects or embodiments, the detecting includes detecting a fragment of the fusion nucleic acid molecule that includes the breakpoint or fusion junction.

[0059] In some embodiments that may be combined with any of the above aspects or embodiments, the fusion nucleic acid molecule is detected in the sample by one or more of a nucleic acid hybridization assay, an amplification-based assay, a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay, real-time PCR, a screening analysis, fluorescent in situ hybridization (FISH), spectral karyotyping, multicolor FISH (mFISH), comparative genomic hybridization, in situ hybridization, sequence-specific priming (SSP) PCR, high-performance liquid chromatography (HPLC), mass spectrometry genotyping, or sequencing. In some embodiments, the sequencing comprises a massively parallel sequencing (MPS) technique, whole genome sequencing (WGS), whole exome sequencing, targeted sequencing, direct sequencing, or Sanger sequencing technique, and optionally, the massively parallel sequencing (MPS) technique comprises next-generation sequencing (NGS).

[0060] In some embodiments that may be combined with any of the preceding aspects or embodiments, detecting the fusion polypeptide encoded by the fusion nucleic acid molecule comprises detecting a portion of the fusion polypeptide encoded by a fragment of the fusion nucleic acid molecule that includes the breakpoint or fusion junction.

[0061] In some embodiments that may be combined with any of the preceding aspects or embodiments, the fusion polypeptide is detected in the sample by one or more of immunoblotting, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, or mass spectrometry.

[0062] In some embodiments that may be combined with any of the above aspects or embodiments, the method further includes selectively enriching one or more nucleic acids in the sample that contain a nucleotide sequence corresponding to the fusion nucleic acid molecule, wherein the selective enrichment produces an enriched sample. In some embodiments, the selective enrichment comprises (a) combining one or more bait molecules with the sample, thereby hybridizing the one or more bait molecules to one or more nucleic acids in the sample that contain a nucleotide sequence corresponding to the fusion nucleic acid molecule to produce nucleic acid hybrids, and (b) isolating the nucleic acid hybrids to produce an enriched sample.

[0063] In some embodiments that may be combined with any of the above aspects or embodiments, one or more bait molecules comprise a capture nucleic acid molecule configured to hybridize to a nucleotide sequence corresponding to the fusion nucleic acid molecule. In some embodiments, the capture nucleic acid molecule comprises about 10 to about 30 nucleotides, about 50 to about 1000 nucleotides, about 100 to about 500 nucleotides, about 100 to about 300 nucleotides, or about 100 to about 200 nucleotides. In some embodiments, the one or more bait molecules are conjugated to an affinity reagent or a detection reagent. In some embodiments, the affinity reagent is an antibody, an antibody fragment, or biotin, or the detection reagent is a fluorescent marker. In some embodiments, the capture nucleic acid molecule comprises DNA, RNA, or a mixed DNA / RNA molecule.

[0064] In some embodiments that may be combined with any of the above aspects or embodiments, the selectively enriching comprises using polymerase chain reaction (PCR) to amplify one or more nucleic acids comprising a nucleotide sequence corresponding to the fusion nucleic acid molecule to produce the enriched sample.

[0065] In some embodiments that may be combined with any of the above aspects or embodiments, the method further comprises sequencing the enriched sample.

[0066] In some embodiments that may be combined with any of the preceding aspects or embodiments, the individual is a human.

[0067] In another aspect, provided herein are kits comprising probes or baits for detecting (i) an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in any of Tables 1 and 3-5, or a fragment thereof comprising a breakpoint or fusion junction, or (ii) an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2 or 6, or a fragment thereof comprising a breakpoint or fusion junction, in a sample from an individual with cancer corresponding to an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2 or 6.

[0068] In another aspect, provided herein is a nucleic acid molecule comprising an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in any of Tables 1 and 3-5, or a fragment thereof comprising a breakpoint or fusion junction.

[0069] In another aspect, provided herein is a vector comprising a nucleic acid described herein.

[0070] In another aspect, provided herein is a host cell comprising a vector provided herein.

[0071] In another aspect, provided herein is an antibody or antibody fragment that specifically binds to a fusion polypeptide or a portion thereof encoded by an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in any of Tables 1 and 3-5, or a fragment thereof comprising a breakpoint or fusion junction.

[0072] In another aspect, provided herein are kits comprising an antibody or antibody fragment for detecting (i) a fusion polypeptide or portion thereof encoded by an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in any of Tables 1 and 3-5, or a fragment thereof comprising a breakpoint or fusion junction, or (ii) a fusion polypeptide or portion thereof encoded by an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2 or 6, in a sample from an individual with a cancer corresponding to an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2 or 6.

[0073] In another aspect, provided herein is in vitro use of one or more oligonucleotides to detect (i) an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in any of Tables 1 and 3-5, or a fragment thereof comprising a breakpoint or fusion junction, or (ii) an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2 or 6, or a fragment thereof comprising a breakpoint or fusion junction, in a sample from an individual having a cancer corresponding to an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2 or 6.

[0074] In another aspect, provided herein are kits comprising one or more oligonucleotides for detecting (i) an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in any of Tables 1 and 3-5, or a fragment thereof comprising a breakpoint or fusion junction, or (ii) an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2 or 6, or a fragment thereof comprising a breakpoint or fusion junction, in a sample from an individual with a cancer corresponding to an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2 or 6.

[0075] In another aspect, provided herein is a system comprising: a memory configured to store one or more program instructions; and one or more processors configured to execute the one or more program instructions, the one or more program instructions, when executed by the one or more processors, are configured to: (a) obtain a plurality of sequence reads for one or more nucleic acid molecules, wherein the one or more nucleic acid molecules are derived from a sample obtained from the individual; (b) analyze the plurality of sequence reads for the presence of a fusion nucleic acid molecule, wherein the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1; and (c) detect the fusion nucleic acid molecule in the sample based on the analysis.

[0076] In another aspect, provided herein is a non-transitory computer-readable storage medium comprising one or more programs executable by one or more computer processors for executing a method, the method comprising: (a) obtaining, using one or more processors, a plurality of sequence reads of one or more nucleic acid molecules, wherein the one or more nucleic acid molecules are derived from a sample obtained from the individual; (b) analyzing, using the one or more processors, the plurality of sequence reads for the presence of a fusion nucleic acid molecule, wherein the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1; and (c) detecting, using the one or more processors, the fusion nucleic acid molecule in the sample based on the analysis.

[0077] In some embodiments that may be combined with any of the above aspects or embodiments, the sample is from an individual with cancer. In some embodiments, the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1, and the ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1 comprises or results from breakpoint 1 and / or breakpoint 2 corresponding to the ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 3. In some embodiments, the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1, and the cancer is carcinoma, sarcoma, lymphoma, leukemia, myeloma, germ cell carcinoma, or blastoma. In some embodiments, the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1, and the cancer is a solid tumor. In some embodiments, the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1, and the cancer is a hematological malignancy.In some embodiments, the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1, and the cancer is B-cell cancer (multiple myeloma), melanoma, breast cancer, lung cancer, bronchial cancer, colorectal cancer, prostate cancer, pancreatic cancer, stomach cancer, ovarian cancer, urinary bladder cancer, brain cancer, central nervous system cancer, peripheral nervous system cancer, esophageal cancer, cervical cancer, uterine cancer, endometrial cancer, oral cavity cancer, pharyngeal cancer, liver cancer, kidney cancer, testicular cancer, biliary tract cancer, small intestine cancer, appendix cancer, salivary gland cancer, thyroid cancer, cancer), adrenal cancer, osteosarcoma, chondrosarcoma, cancer of the blood tissue, adenocarcinoma, inflammatory myofibroblastic tumor, gastrointestinal stromal tumor (GIST), colon cancer, multiple myeloma (MM), myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), polycythemia vera, Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL) ), soft tissue sarcoma, fibrosarcoma, myxosarcoma, liposarcoma, osteosarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, medullary carcinoma, bronchogenic lung carcinoma, renal cell carcinoma, hepatocellular carcinoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, bladder cancer carcinoma), epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, retinoblastoma, follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, hepatocellular carcinoma, thyroid cancer, gastric cancer, head and neck cancer, small cell carcinoma, essential thrombocythemia, primary myelofibrosis, hypereosinophilic syndrome, systemic mastocytosis, familial hypereosinophilia, chronic eosinophilic leukemia, neuroendocrine carcinoma, or carcinoid tumor.In some embodiments, the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1, and the cancer is appendix adenocarcinoma, bladder adenocarcinoma, bladder urothelial (transitional cell) carcinoma, NOS breast cancer not otherwise specified, NOS breast carcinoma, invasive ductal carcinoma (IDC), breast invasive lobular carcinoma (ILC), cervical squamous cell carcinoma (SCC), colon adenocarcinoma (CRC), esophageal adenocarcinoma, NOS esophageal carcinoma, esophageal squamous cell carcinoma (SCC), intraocular melanoma, gallbladder adenocarcinoma, gastroesophageal junction adenocarcinoma, intrahepatic cholangiocarcinoma, NOS kidney cancer, liver hepatocellular carcinoma (HCC), NOS lung cancer, lung adenocarcinoma, lung large cell carcinoma, NOS non-small cell lung cancer (NSCLC), lung undifferentiated small cell carcinoma. alveolar carcinoma, lung squamous cell carcinoma (SCC), NOS ovarian cancer, NOS pancreatic cancer, pancreatic ductal adenocarcinoma, pancreaticobiliary carcinoma, NOS prostate cancer, prostatic acinar adenocarcinoma, prostatic ductal adenocarcinoma, rectal adenocarcinoma (CRC), cutaneous melanoma, small intestine adenocarcinoma, NOS soft tissue sarcoma, NOS gastric adenocarcinoma, NOS carcinoma of unknown primary, adenocarcinoma of unknown primary, NOS carcinoma of unknown primary (CUP), neuroendocrine tumor of unknown primary, squamous cell carcinoma (SCC) of unknown primary, or NOS endometrial adenocarcinoma.In some embodiments, (a) the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1 and the cancer is a cancer corresponding to an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 4, or (b) the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1. and the cancer is a cancer corresponding to an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 5, and the fusion nucleic acid molecule comprises or results from breakpoint 1 and / or breakpoint 2 corresponding to an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 5.

[0078] In another aspect, provided herein is a system comprising: a memory configured to store one or more program instructions; and one or more processors configured to execute the one or more program instructions, the one or more program instructions, when executed by the one or more processors, are configured to: (a) obtain a plurality of sequence reads of one or more nucleic acid molecules, wherein the one or more nucleic acid molecules are derived from a sample obtained from an individual having cancer; (b) analyze the plurality of sequence reads for the presence of a fusion nucleic acid molecule, wherein the fusion nucleic acid molecule is an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2, and the cancer is a cancer corresponding to the ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2; and (c) detect the fusion nucleic acid molecule in the sample based on the analysis.

[0079] In another aspect, provided herein is a non-transitory computer-readable storage medium comprising one or more programs executable by one or more computer processors for executing a method, the method comprising: (a) obtaining, using one or more processors, a plurality of sequence reads of one or more nucleic acid molecules, wherein the one or more nucleic acid molecules are derived from a sample obtained from an individual with cancer; (b) analyzing, using one or more processors, the plurality of sequence reads for the presence of a fusion nucleic acid molecule, wherein the fusion nucleic acid molecule is an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2, and the cancer is a cancer corresponding to the ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2; and (c) detecting, using the one or more processors, the fusion nucleic acid molecule in the sample based on the analysis.

[0080] In some embodiments that may be combined with any of the preceding aspects or embodiments, the fusion nucleic acid molecule comprises or results from breakpoint 1 and / or breakpoint 2 corresponding to an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 6.

[0081] In some embodiments that may be combined with any of the above aspects or embodiments, the plurality of sequence reads are obtained by sequencing, and optionally, the sequencing comprises use of a massively parallel sequencing (MPS) technique, whole genome sequencing (WGS), whole exome sequencing, targeted sequencing, direct sequencing, or Sanger sequencing technique, and optionally, the massively parallel sequencing technique comprises next-generation sequencing (NGS).

[0082] In some embodiments that may be combined with any of the above aspects or embodiments, the one or more program instructions, when executed by the one or more processors, are further configured to generate a genomic profile for the sample based at least in part on the detection.

[0083] In some embodiments that may be combined with any of the above aspects or embodiments, the method further includes generating a genomic profile for the sample based at least in part on the detecting.

[0084] In some embodiments that may be combined with any of the above aspects or embodiments, the individual is administered a treatment that is based at least in part on the genomic profile.

[0085] In some embodiments that may be combined with any of the above aspects or embodiments, the genomic profile further comprises results from a comprehensive genomic profiling (CGP) test, a gene expression profiling test, a cancer hotspot panel test, a DNA methylation test, a DNA fragmentation test, an RNA fragmentation test, or any combination thereof. In some embodiments that may be combined with any of the above aspects or embodiments, the genomic profile further comprises results from a nucleic acid sequencing-based test.

[0086] In another aspect, an anti-cancer therapy for use in a method for treating or delaying the progression of cancer, the method comprising administering the anti-cancer therapy to an individual, wherein (a) an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1, or a fragment thereof comprising a breakpoint or fusion junction, or a fusion polypeptide encoded by the fusion nucleic acid molecule, is detected in a sample obtained from the individual; or (b) an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1, or a fragment thereof comprising a breakpoint or fusion junction, or a fusion polypeptide encoded by the fusion nucleic acid molecule, is detected in a sample obtained from the individual. Provided herein are anti-cancer therapies wherein a BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule, or a fragment thereof comprising a breakpoint or fusion junction, or a fusion polypeptide encoded by the fusion nucleic acid molecule, is detected in a sample obtained from an individual, wherein the individual has a cancer corresponding to an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2.

[0087] In another aspect, there is provided an anti-cancer therapy for use in the manufacture of a medicament for treating or slowing the progression of cancer, wherein the medicament is administered to an individual and (a) an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1, or a fragment thereof comprising a breakpoint or fusion junction, or a fusion polypeptide encoded by the fusion nucleic acid molecule, is detected in a sample obtained from the individual; or (b) an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2 is detected in a sample obtained from the individual. Provided herein are anti-cancer therapies wherein an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule, or a fragment thereof comprising a breakpoint or fusion junction, or a fusion polypeptide encoded by the fusion nucleic acid molecule, is detected in a sample obtained from an individual, wherein the individual has a cancer corresponding to an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2.

[0088] It should be understood that one, some, or all of the features of the various embodiments described herein may be combined to form other embodiments of the present invention. These and other aspects of the present invention will become apparent to those skilled in the art. These and other embodiments of the present invention are further described in the detailed description that follows. [Brief explanation of the drawings]

[0089] [Figure 1A-1B] Figure 1 shows the results of a hybrid capture-based comprehensive genomic profiling (CGP) assay for detecting kinase fusions in circulating tumor DNA (ctDNA) across various cancer types, as described in Examples 1-3. Figure 1A shows the frequency (percentage shown on the x-axis) of kinase fusions detected in ctDNA in each of the cancer types shown on the y-axis. The number in each bar indicates the total number of unique samples with kinase fusions in this tumor type. Figure 1B shows a heat map of kinase fusions detected in the indicated cancer types. The shading ("fusion count") in the figure legend on the right indicates the number of fusions for each of the kinases on the vertical axis identified in the cancer type on the horizontal axis. Bile duct = cholangiocarcinoma; NSCLC = non-small cell lung cancer; CUP = carcinoma of unknown primary; CRC = colorectal cancer; NOS = not specified. [Figure 2A-2B] This figure provides an overview of the most frequent kinase fusion partners identified in ctDNA across various cancer types, as well as the locations of the identified fusion breakpoints. Figure 2A shows a pie chart representing the most frequent fusions identified in each of the indicated cancer types. Figure 2B shows a lollipop plot of the locations of the identified fusion breakpoints in the indicated kinases. [Figure 3] Figure 1 shows the frequency of kinase fusions involving the indicated kinases (FGFR2, BRAF, FGFR3, ROS1, RET, and ALK) identified in tissue biopsies (percentages shown on the y-axis) and liquid biopsies (percentages shown on the x-axis) in NSCLC. Arrows indicate statistical significance (p≦0.05). [Figure 4]1 provides a summary of the analysis of concordance between kinase fusions identified in ctDNA (liquid biopsies; n=571) and tissue (tissue biopsies; n=7,599), as described in Example 2. [Figure 5] Sensitivity (positive concordance rate [PPA]) (y-axis) for detecting kinase fusions in cases with both tissue and liquid biopsy results for each of the x-axis groups is shown. Of 4,722 tissue-ctDNA concordant pairs, 169 pairs harbored the fusion in either the tissue or liquid specimen. PPAs for disease- and kinase-specific subsets with at least 20 pairs are shown. BBLB1 = Blood-Based Liquid Biopsy Assay #1. [Figure 6] Figure 1 shows the effect of ctDNA fraction on the concordance of kinase fusions identified in liquid and tissue biopsies. The y-axis shows the estimated ctDNA fraction (as a percentage; calculated as described in Example 2) for each of the groups listed on the x-axis. "Concordance" refers to cases in which the same kinase fusion was identified in both liquid and tissue biopsies. "Tissue negative" refers to cases in which the kinase fusion was identified only in the liquid biopsy (not in the tissue biopsy). "Liquid negative" refers to cases in which the kinase fusion was identified only in the tissue biopsy (not in the liquid biopsy). The arrow indicates the median ctDNA fraction. [Figures 7A-7B]Figure 7A shows the sensitivity (positive agreement rate [PPA]) for kinase fusion detection in cases with both tissue and liquid biopsy CGP results. Figure 7A shows the sensitivity (PPA) (y-axis) for detecting kinase fusions in ctDNA in each estimated ctDNA fraction in liquid biopsies shown on the x-axis for any cancer type ("All Pairs"; n = 169) or NSCLC (n = 103). The number above each bar indicates the number of tissue and liquid biopsy pairs with fusions identified in the tissue or liquid biopsy. Figure 7B shows the sensitivity (PPA) (y-axis) for detecting kinase fusions in ctDNA in each time frame between tissue and liquid specimen collection (less than one year or more than one year between collection of tissue and liquid biopsy samples) shown on the x-axis for any cancer type ("All Pairs"; n = 106) or NSCLC (n = 59). The number above each bar indicates the number of tissue and liquid biopsy pairs with fusions identified in the tissue or liquid biopsy. [Figure 8] Figure 1 shows the effect of time between specimen collections on the concordance between kinase fusions identified in liquid and tissue biopsies. The y-axis shows the number of days between liquid and tissue biopsy specimen collections, calculated as described in Example 2, for each of the groups listed on the x-axis. "Concordance" refers to cases in which the same kinase fusion was identified in both the liquid and tissue biopsies. "Tissue negative" refers to cases in which the kinase fusion was identified only in the liquid biopsy (not in the tissue biopsy). "Liquid negative" refers to cases in which the kinase fusion was identified only in the tissue biopsy (not in the liquid biopsy). The arrows indicate the median number of days between specimen collections. [Figure 9] Figure 1 shows ALK fusions identified in liquid biopsy specimens with known ALK resistance mutations. The legend and top of the figure indicate the gene fusion partner (e.g., "EML4" indicates an ALK-EML4 kinase fusion). ALK mutations identified in samples containing each of the indicated ALK fusions are shown as shaded boxes. An asterisk indicates the presence of the EGFR L858R mutation. [Figure 10] 1 illustrates an exemplary device according to some embodiments. [Figure 11]1 illustrates an exemplary system according to some embodiments. [Figure 12] FIG. 1 shows a block diagram of an exemplary process for detecting a fusion nucleic acid molecule, according to some embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0090] The present disclosure relates generally to the detection of kinase fusions in cancer and related therapeutic methods and uses.

[0091] Kinase fusions are an important class of targetable oncogenic driver variants. This disclosure describes the study of real-world datasets containing high-quality validated hybrid capture-based next-generation sequencing (NGS) results that characterized the pan-cancer landscape of kinase fusions, including ALK, BRAF, EGFR, ERBB2, FGFR1 / 2 / 3, MET, NTRK1 / 2 / 3, PDGFRA / B, RAF1, RET, and ROS1 kinases, in circulating tumor DNA (ctDNA) and tumor tissue samples. As described herein, applicants discovered numerous kinase fusions across diverse cancer types, cancer genes, and breakpoints, and unexpectedly found at least 571 kinase fusions in ctDNA samples. See, e.g., Example 1. Advantageously, genomic profiling of ctDNA closely reproduced the results of tissue-based testing, with the majority of discrepancies between tissue and ctDNA results attributable to a combination of biological and / or analytical factors. See, e.g., Example 2. Applicant has further unexpectedly discovered that analysis of ctDNA, e.g., analysis of ctDNA from liquid biopsies, has identified targetable kinase fusions associated with acquired resistance to anti-cancer therapies. See, e.g., Example 3. Thus, without wishing to be bound by theory, it is believed that the presence of a kinase fusion described herein in a sample from an individual with cancer, e.g., a liquid biopsy sample containing ctDNA, and / or a tissue sample, e.g., a tumor biopsy, may identify cancer patients who are more likely to respond to treatment with an anti-cancer therapy, e.g., a targeted anti-cancer therapy, such as those described herein.

[0092] I. General Techniques The techniques and procedures described or referenced herein generally conform to conventional methodology, e.g., those described in Sambrook et al., Molecular Cloning: A Laboratory Manual 3rd edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, Current Protocols in Molecular Biology (F.M.A.usubel, et al., eds., (2003)), the series Methods in Enzymology (Academic Press, Inc.): PCR 2: A Practical Approach (M.J.MacPherson, B.D.Hames and G.R.Taylor, eds., (1995)), Antibodies, A Laboratory Manual (Harlow and Lane, eds., (1988)), and Animal Cell Culture (R.I. Freshney, ed., (1987)), Oligonucleotide Synthesis (M.J.Gait, ed., 1984), Methods in Molecular Biology, Humana Press, Cell Biology: A Laboratory Notebook (J.E.Cellis, ed., 1998) Academic Press, Animal Cell Culture (RIFreshney), 1987), Introduction to Cell and Tissue Culture (JPMather and PE Roberts, 1998), Plenum Press, Cell and Tissue Culture: Laboratory Procedures (A. Doyle, JBGriffiths, and DG Newell, eds., 1993-8), J. Wiley and Sons, Handbook of Experimental Immunology (DMWeir and CC Blackwell, eds.), Gene Transfer. Vectors for Mammalian Cells(JMMiller and MPCalos, 1987), PCR: The Polymerase Chain Reaction, (Mullis et al., 1994), Current Protocols in Immunology (JEColigan et al., 1991), Short Protocols in Molecular Biology (Wiley and Sons, 1999), Immunobiology (CA Janeway and P. Travers, 1997), Antibodies (P. Finch, 1997), Antibodies: A Practical Approach (edited by D. Catty, IRL Press, 1988-1989), Monoclonal Antibodies: A Practical Approach (edited by P. Shepherd and C. Dean, Oxford University Press, 2000), Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999), The Antibodies (edited by M. Zanetti and JD Capra, Harwood Academic Publishers, 1995), as well as widely used methodologies described in Cancer: Principles and Practice of Oncology (V.T. DeVita et al., eds., J.B. Lippincott Company, 1993), are well understood and commonly used by those skilled in the art.

[0093] II. Definition As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a molecule" optionally includes a combination of two or more such molecules, and the like.

[0094] The term "about" as used herein refers to a normal error range for the respective value, readily known to one of ordinary skill in the art. Reference herein to "about" a value or parameter includes (and describes) embodiments that are directed to the value or parameter itself.

[0095] It is understood that aspects and embodiments of the invention described herein include "comprising," "consisting of," and / or "consisting essentially of" aspects and embodiments.

[0096] The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. This definition includes benign and malignant cancers.

[0097] As used herein, the term "tumor" refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. The terms "cancer," "cancerous," and "tumor" are not mutually exclusive when referred to herein.

[0098] As used interchangeably herein, the terms "polynucleotide," "nucleic acid," or "nucleic acid molecule" refer to a polymer of nucleotides of any length, including DNA and RNA. Nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase or by a synthetic reaction. Thus, for example, polynucleotides as defined herein include, but are not limited to, single- and double-stranded DNA, DNA containing single- and double-stranded regions, single- and double-stranded RNA, RNA containing single- and double-stranded regions, and hybrid molecules containing DNA and RNA that may be single-stranded or typically double-stranded, or that contain single- and double-stranded regions. Additionally, as used herein, the term "polynucleotide" refers to triple-stranded regions containing RNA or DNA, or both RNA and DNA. The strands in such regions may be from the same molecule or from different molecules. A region may include all of one or more of the molecules, but more typically involves only some regions of a molecule. One of the molecules in the triple helix region is often an oligonucleotide. The term "polynucleotide" specifically includes cDNA.

[0099] A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and their analogs. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after synthesis, such as by conjugation with a label. Other types of modifications include, for example, substitution of one or more of the naturally occurring nucleotides with "caps," analogs, internucleotide modifications, such as those with uncharged linkages (e.g., methylphosphonates, phosphotriesters, phosphoamidates, carbamates, etc.) and those with charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.), those containing pendant moieties, such as proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.), those with intercalators (e.g., acridine, psoralens, etc.), those containing chelators (e.g., metals, radioactive metals, boron, metal oxides, etc.), those containing alkylators, those with modified linkages (e.g., alpha-anomeric nucleic acids), and unmodified forms of polynucleotides. Additionally, any of the hydroxyl groups normally present in the sugar may be replaced, for example, by phosphonate groups, phosphate groups, protected by standard protecting groups, or activated to prepare additional linkages for additional nucleotides, or conjugated to solid or semi-solid supports. The 5'- and 3'-terminal OH groups may be phosphorylated or substituted with amines or organic capping group moieties of 1 to 20 carbon atoms. Other hydroxyls may also be derivatized to standard protecting groups. Polynucleotides may also contain analogous forms of ribose or deoxyribose sugars commonly known in the art, including, for example, 2'-O-methyl-, 2'-O-allyl-, 2'-fluoro-, or 2'-azido-ribose, carbocyclic sugar analogs, α-anomeric sugars, epimeric sugars such as arabinose, xylose, or lyxose, pyranose sugars, furanose sugars, sedoheptuloses, acyclic analogs, and abasic nucleoside analogs such as methyl riboside.One or more phosphodiester linkages may be replaced by alternative linking groups. These alternative linking groups include, but are not limited to, embodiments in which phosphate is replaced by P(0)S ("thioate"), P(S)S ("dithioate"), P(0)NR2 ("amidate"), P(0)R, P(0)OR', CO, or CH2 ("formacetal"), where each R or R' is independently H or substituted or unsubstituted alkyl (1-20C), optionally containing an ether (-0-) linkage, aryl, alkenyl, cycloalkyl, cycloalkenyl, or araldyl. Not all linkages in a polynucleotide need be identical. A polynucleotide can contain one or more different types of modifications described herein and / or multiple modifications of the same type. The foregoing description applies to all polynucleotides referred to herein, including RNA and DNA.

[0100] As used herein, "oligonucleotide" generally refers to a short, single-stranded polynucleotide, generally, but not necessarily, less than about 250 nucleotides in length. An oligonucleotide may be synthetic. The terms "oligonucleotide" and "polynucleotide" are not mutually exclusive. The above description of polynucleotides is equally and fully applicable to oligonucleotides.

[0101] The term "antibody" as used herein is used in the broadest sense and encompasses a variety of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired antigen-binding activity.

[0102] An "isolated" antibody is one that has been identified and separated and / or recovered from a component of its natural environment. Contaminant components of its natural environment are materials that may interfere with research, diagnostic, and / or therapeutic uses of the antibody, and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In some embodiments, the antibody is purified (1) to greater than 95%, and in some embodiments, greater than 99%, by weight of the antibody, e.g., as determined by the Lowry method; (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence, e.g., by use of a spinning cup sequencer; or (3) to homogeneity by SDS-PAGE under reducing or non-reducing conditions, e.g., using Coomassie blue or silver staining. Isolated antibodies include the antibody in situ within recombinant cells, since at least one component of the antibody's natural environment will not be present. Ordinarily, however, isolated antibodies will be prepared by at least one purification step.

[0103] "Native antibodies" are typically heterotetrameric glycoproteins of about 150,000 daltons composed of two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide bonds varies among the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has a variable domain (VH) at one end followed by some number of constant domains. Each light chain has a variable domain (VL) at one end and a constant domain at its other end, with the light-chain constant domain aligned with the first constant domain of the heavy chain and the light-chain variable domain aligned with the variable domain of the heavy chain. Particular amino acid residues are believed to form an interface between the light-chain variable domain and the heavy-chain variable domain.

[0104] The "light chains" of antibodies (immunoglobulins) from any mammalian species can be assigned to one of two clearly distinct types, called kappa ("κ") and lambda ("λ"), based on the amino acid sequences of their constant domains.

[0105] The term "constant domain" refers to a portion of an immunoglobulin molecule having a more conserved amino acid sequence than the other portion of the immunoglobulin, the variable domain, which contains the antigen-binding site. The constant domain contains the CH1, CH2, and CH3 domains (collectively CH) of the heavy chain and the CHL (or CL) domain of the light chain.

[0106] The "variable region" or "variable domain" of an antibody refers to the amino-terminal domain of either the heavy or light chain of the antibody. The variable domain of a heavy chain may be referred to as "VH." The variable domain of a light chain may be referred to as "VL." These domains are generally the most variable parts of an antibody and contain the antigen-binding sites.

[0107] The term "variable" refers to the fact that certain portions of the variable domains differ extensively in sequence among antibodies and are used in the binding and specificity of each particular antibody to its particular antigen. However, variability is not uniformly distributed throughout the variable domains of antibodies. In both the light- and heavy-chain variable domains, it is concentrated in three segments called hypervariable regions (HVRs). The more highly conserved portions of the variable domains are called framework regions (FRs). Native heavy- and light-chain variable domains each contain four FR regions, which largely adopt a beta-sheet configuration and are connected by three HVRs that form connecting loops, and in some cases form part of the beta-sheet structure. The HVRs within each chain are held together in close proximity by the FR regions and, together with HVRs from other chains, contribute to the formation of the antigen-binding site of antibodies (Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, Md. (1991)). The constant domains are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular cytotoxicity.

[0108] As used herein, the terms "hypervariable region," "HVR," or "HV" refer to regions of an antibody variable domain that are hypervariable in sequence and / or form structurally defined loops. Generally, antibodies contain six HVRs: three HVRs in the VH (H1, H2, and H3) and three HVRs in the VL (L1, L2, and L3). In native antibodies, H3 and L3 exhibit the greatest diversity among the six HVRs, and H3 in particular is thought to play a unique role in conferring precise specificity to antibodies. See, e.g., Xu et al., Immunity 13:37-45 (2000); Johnson and Wu in Methods in Molecular Biology 248:1-25 (ed. Lo, Human Press, Totowa, NJ, 2003). In fact, naturally occurring camelid antibodies consisting only of heavy chains are functional and stable in the absence of light chains. See, for example, Hamers-Casterman et al., Nature 363:446-448 (1993); Sheriff et al., Nature Struct. Biol. 3:733-736 (1996).

[0109] A summary description of a number of HVRs is used and is encompassed herein. Kabat complementarity-determining regions (CDRs) are based on sequence diversity and are most commonly used (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). Chothia, instead, refers to the location of the structural loops (Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)). AbM HVRs represent the complement between Kabat HVRs and Chothia structural loops and are used by Oxford Molecular's AbM antibody modeling software. "Contact" HVRs are based on analysis of available complex crystal structures. Residues from each of these HVRs are shown below. [Table 1]

[0110] HVRs may include "extended HVRs" as follows: within VL, 24-36 or 24-34 (L1), 46-56 or 50-56 (L2), and 89-97 or 89-96 (L3), and within VH, 26-35 (H1), 50-65 or 49-65 (H2), and 93-102, 94-102, or 95-102 (H3). The variable domain residues are numbered for each of these definitions according to Kabat et al., supra.

[0111] "Framework" or "FR" residues are those variable domain residues other than the HVR residues as herein defined.

[0112] "Kabat variable domain residue numbering" or "Kabat amino acid position numbering," and variations thereof, refer to the numbering system used for the heavy or light chain variable domains of the antibody collection in Kabat et al., supra. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of the variable domain or an insertion into the FR or HVR of the variable domain. For example, a heavy chain variable domain may contain a single amino acid insertion after residue 52 of H2 (residue 52a according to Kabat) and inserted residues after heavy chain FR residue 82 (e.g., residues 82a, 82b, and 82c according to Kabat). The Kabat numbering of residues can be determined for a given antibody by alignment with a "standard" Kabat-numbered sequence at regions of antibody sequence homology.

[0113] The Kabat numbering system is generally used when referring to residues within the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain) (e.g., Kabat et al., Sequences of Immunological Interest. 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). The "EU numbering system" or "EU index" is generally used when referring to residues in immunoglobulin heavy chain constant regions (e.g., the EU index reported in Kabat et al., supra). "EU index as per Kabat" refers to the residue numbering of the human IgG1 EU antibody.

[0114] The terms "full-length antibody," "intact antibody," and "whole antibody" are used interchangeably herein and refer to an antibody in substantially intact form, rather than an antibody fragment as defined below. This term particularly refers to an antibody having a heavy chain containing an Fc region.

[0115] An "antibody fragment" includes a portion of an intact antibody that contains its antigen-binding region. In one embodiment, the antibody fragments described herein are antigen-binding fragments. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.

[0116] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous antibody population, e.g., the individual antibodies comprising the population are identical except for possible variations that may be present in minor amounts, e.g., naturally occurring variations. Thus, the modifier "monoclonal" indicates the character of the antibody as not being a mixture of distinct antibodies. In certain embodiments, such monoclonal antibodies typically comprise an antibody comprising a polypeptide sequence that binds to a target, where the target-binding polypeptide sequence was obtained by a process that includes selection of a single target-binding polypeptide sequence from a plurality of polypeptide sequences. For example, the selection process can be selection of a unique clone from a pool of multiple clones, e.g., hybridoma clones, phage clones, or recombinant DNA clones. It should be understood that the selected target-binding sequence can be further altered, e.g., to improve affinity for the target, humanize the target-binding sequence, improve its production in cell culture, reduce its immunogenicity in vivo, create multispecific antibodies, etc., and that antibodies comprising altered target-binding sequences are also monoclonal antibodies of the invention. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on the antigen. In addition to their specificity, monoclonal antibody preparations are advantageous in that they are typically uncontaminated by other immunoglobulins.

[0117] The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies used in accordance with the present invention can be produced using, for example, hybridoma methods (e.g., Kohler and Milstein, Nature 256:495-97 (1975); Hongo et al., Hybridoma 14(3):253-260 (1995); Harlow et al., Antibodies: A Laboratory Manual (Cold Spring Harbor Laboratory Press, 2nd ed. 1988); Hammerling et al., in: Monoclonal Antibodies and T-Cell Hybridomas 563-681 (Elsevier, NY, 1981)), recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567), phage display techniques (e.g., Clackson et al., Nature, 352:624-628 (1991); Marks et al. al., J.Mol.Biol.222:581-597(1992), Sidhu et al., J.Mol.Biol.338(2):299-31 0(2004), Lee et al. al., J.Mol.Biol.340(5):1073-1093(2004), Fellouse,Proc.Natl.Acad.Sci.USA 101(34):12467-12472(2004), and Lee et al.,J.Immunol.Methods 284(1-2):1 1 9-132 (2004)), and techniques for producing human or human-like antibodies in animals having portions or all of the human immunoglobulin loci or genes encoding human immunoglobulin sequences (e.g., WO1998 / 24893, WO1996 / 34096, WO1996 / 33735, WO1991 / 10741, Jakobovits et al., Proc. Natl. Acad. Sci. USA 90:2551 (1993), Jakobovits et al., Nature 362:255-258 (1993), Bruggemann et al., Year in Immunol. 7:33 (1993), U.S. Patent Nos. 5,545,807, 5,545,806, 5,569,825, 5,625,126, 5,633,425, and 5,661,016, Marks et al., Bio / Technology 10:779-783 (1992), Lonberg et al., Nature 368:856-859 (1994), Morrison, Nature 368:812-813 (1994), Fishwild et al., Nature Biotechnol. 14:845-851 (1996), Neuberger, Nature Biotechnol. 14:826 (1996), and Lonberg et al. These antibodies can be produced by a variety of techniques, including by ion implantation (see, e.g., J. Med. Chem. Soc., 1995, 13:65-93).

[0118] A "human antibody" is one having an amino acid sequence that corresponds to that of an antibody produced by a human or a human cell, or an antibody derived from a non-human source that uses a human antibody repertoire or other human antibody coding sequence. This definition of a human antibody specifically excludes humanized antibodies that contain non-human antigen-binding residues.

[0119] A "humanized" antibody refers to a chimeric antibody comprising amino acid residues from non-human HVRs and amino acid residues from human framework regions (FRs). In certain embodiments, a humanized antibody comprises substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g., CDRs) correspond to those of a non-human antibody and all or substantially all of the FRs correspond to those of a human antibody. A humanized antibody may optionally comprise at least a portion of an antibody constant region derived from a human antibody.

[0120] A "humanized form" of an antibody, eg, a non-human antibody, refers to an antibody that has been subjected to humanization.

[0121] A "blocking" or "antagonist" antibody is one that inhibits or reduces the biological activity of the antigen to which it binds. For example, a blocking or antagonist antibody substantially or completely inhibits the biological activity of the antigen.

[0122] As used herein, the terms "bind," "specifically bind to," or "specific for" refer to a measurable and reproducible interaction, e.g., binding between a target and an antibody, that determines the presence of the target in the presence of a heterogeneous population of molecules, including biological molecules. For example, an antibody that binds to or specifically binds to a target (which may be an epitope) is one that binds to this target more readily, with greater affinity, avidity, and / or with greater duration than it binds to other targets. In one embodiment, the extent of binding of an antibody to an unrelated target is less than about 10% of the binding of the antibody to the target, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, an antibody that specifically binds to a target has a dissociation constant (Kd) of less than 1 μM, less than 100 nM, less than 10 nM, less than 1 nM, or less than 0.1 nM. In certain embodiments, an antibody specifically binds to an epitope on a protein that is conserved among proteins from different species. In another embodiment, specific binding can, but need not, include exclusive binding.

[0123] "Percent (%) amino acid sequence identity" for a polypeptide sequence specified herein is defined as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in the polypeptide being compared, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, without considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in a variety of ways within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, ALIGN-2, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms required to achieve maximum alignment over the entire length of the sequences being compared.

[0124] The term "detection" includes any means of detection, including direct and indirect detection. As used herein, the term "biomarker" (e.g., a "biomarker" such as a kinase fusion or fusion nucleic acid molecule or polypeptide described herein) refers to an indicator that can be detected in a sample, e.g., a predictive, diagnostic, and / or prognostic indicator. A biomarker can serve as an indicator of a particular subtype of a disease or disorder (e.g., cancer) characterized by certain molecular, pathological, histological, and / or clinical characteristics (e.g., responsiveness to therapy, including checkpoint inhibitors). In one embodiment, a biomarker is a set of genes or a set number of mutations / alterations (e.g., somatic mutations) in a set of genes. Biomarkers include, but are not limited to, molecular markers of polynucleotides (e.g., DNA and / or RNA), polynucleotide alterations (e.g., polynucleotide copy number alterations, e.g., DNA copy number alterations), polypeptides, modifications of polypeptides and polynucleotides (e.g., post-translational modifications), carbohydrates, and / or glycolipids.

[0125] As used herein, "amplification" generally refers to the process of producing multiple copies of a desired sequence. "Multiple copies" means at least two copies. "Copy" does not necessarily imply perfect sequence complementarity or identity with the template sequence. For example, copies may contain nucleotide analogs such as deoxyinosine, intentional sequence variations (e.g., sequence variations introduced by primers containing sequences that are hybridizable to but not complementary to the template), and / or sequence errors that occur during amplification.

[0126] As used herein, the technique of "polymerase chain reaction" or "PCR" generally refers to a procedure in which small amounts of specific nucleic acids, RNA, and / or DNA fragments are amplified, as described, for example, in U.S. Pat. No. 4,683,195. Generally, sequence information from or beyond the ends of the region of interest must be available so that oligonucleotide primers can be designed that are identical or similar in sequence to opposite strands of the template to be amplified. The 5' terminal nucleotides of the two primers may correspond to the ends of the amplified material. PCR can be used to amplify specific RNA sequences, specific DNA sequences from total genomic DNA, and cDNA transcribed from total cellular RNA, bacteriophage, or plasmid sequences, etc. See generally Mullis et al., Cold Spring Harbor Symp. Quant. Biol. 51:263 (1987), and Erlich (ed.), PCR Technology (Stockton Press, NY, 1989). As used herein, PCR is considered to be one example, but not the only example, of a nucleic acid polymerase reaction method for amplifying a nucleic acid test sample that involves the use of known nucleic acids (DNA or RNA) as primers and a nucleic acid polymerase to amplify or generate a specific piece of nucleic acid, or a specific piece of nucleic acid that is complementary to the specific nucleic acid.

[0127] The term "diagnosis" is used herein to refer to the identification or classification of a molecular or pathological state, disease, or condition (e.g., cancer). For example, "diagnosis" can refer to the identification of a particular type of cancer. "Diagnosis" can also refer to the classification of a particular subtype of cancer, for example, by histopathological criteria or by molecular features (e.g., a subtype characterized by the expression of one or a combination of biomarkers (e.g., particular genes or proteins encoded by those genes)).

[0128] The term "aiding in diagnosis" is used herein to refer to a method of assisting in making a clinical decision regarding the presence or nature of a particular type of symptom or condition of a disease or disorder (e.g., cancer). For example, a method of aiding in the diagnosis of a disease or condition (e.g., cancer) may involve measuring certain somatic mutations in a biological sample from an individual.

[0129] As used herein, the term "sample" refers to a composition obtained or derived from a subject and / or individual of interest, containing cells and / or other molecular entities that are characterized and / or identified, e.g., based on physical, biochemical, chemical, and / or physiological characteristics. For example, the phrase "disease sample" and variations thereof refer to any sample obtained from a subject of interest that is expected to contain or is known to contain the cells and / or molecular entities to be characterized. Samples include, but are not limited to, tissue samples, primary or cultured cells or cell lines, cell supernatants, cell lysates, platelets, serum, plasma, vitreous fluid, lymphatic fluid, synovial fluid, follicular fluid, semen, amniotic fluid, milk, whole blood, plasma, serum, blood-derived cells, urine, cerebrospinal fluid, saliva, sputum, tears, sweat, mucus, tumor lysates, and tissue culture media, tissue extracts, e.g., homogenized tissue, tumor tissue, cell extracts, and combinations thereof. In some cases, the sample is a whole blood sample, a plasma sample, a serum sample, or a combination thereof. In some embodiments, the sample is from a tumor (e.g., a "tumor sample"), e.g., from a biopsy. In some embodiments, the sample is a formalin-fixed, paraffin-embedded (FFPE) sample.

[0130] As used herein, "tumor cell" refers to any tumor cell present in a tumor or a sample thereof. Tumor cells can be distinguished from other cells, such as stromal cells and tumor-infiltrating immune cells, that may be present in a tumor sample using methods known in the art and / or described herein.

[0131] As used herein, "reference sample," "reference cell," "reference tissue," "control sample," "control cell," or "control tissue" refers to a sample, cell, tissue, standard, or level used for comparison purposes.

[0132] "Correlate" or "correlating," in any case, means comparing the performance and / or results of a first analysis or protocol with the performance and / or results of a second analysis or protocol. For example, the results of the first analysis or protocol may be used in performing a second protocol and / or to determine whether to perform a second analysis or protocol. With respect to polypeptide analysis or protocol embodiments, the results of the polypeptide expression analysis or protocol may be used to determine whether to perform a particular therapeutic regimen. With respect to polynucleotide analysis or protocol embodiments, the results of the polynucleotide expression analysis or protocol may be used to determine whether to perform a particular therapeutic regimen.

[0133] "Individual response" or "response" can be assessed using any endpoint that indicates benefit to an individual, including, but not limited to, (1) inhibition to some extent, including slowing or complete halting, of disease progression (e.g., cancer progression); (2) reduction in tumor size; (3) inhibition (i.e., reduction, slowing, or complete halt) of cancer cell invasion into adjacent peripheral organs and / or tissues; (4) inhibition (i.e., reduction, slowing, or complete halt) of metastasis; (5) alleviation to some extent of one or more symptoms associated with a disease or disorder (e.g., cancer); (6) increase or prolongation in length of survival, including overall survival and progression-free survival; and / or (7) reduced mortality at a given time point after treatment.

[0134] An "effective patient response" or patient "responsiveness," and similar phrases, to treatment with a pharmaceutical agent refers to a clinical or therapeutic benefit conferred on a patient at risk for or suffering from a disease or disorder, e.g., cancer. In one embodiment, such benefit includes any one or more of: prolonging survival (including overall survival and / or progression-free survival); producing an objective response (including a complete or partial response); or ameliorating the signs or symptoms of cancer.

[0135] An "effective amount" refers to the amount of a therapeutic agent to treat or prevent a disease or disorder in a mammal. In the case of cancer, a therapeutically effective amount of a therapeutic agent may reduce the number of cancer cells, reduce primary tumor size, inhibit (i.e., slow to some extent, and in some embodiments, halt) cancer cell invasion into peripheral organs, inhibit (i.e., slow to some extent, and in some embodiments, halt) tumor metastasis, inhibit tumor growth to some extent, and / or alleviate to some extent one or more symptoms associated with the disorder. To the extent a drug may prevent growth and / or kill existing cancer cells, the drug may be cytostatic and / or cytotoxic. In the case of cancer therapy, in vivo efficacy can be measured, for example, by assessing duration of survival, time to disease progression (TTP), response rate (e.g., CR or PR), duration of response, and / or quality of life.

[0136] The term "pharmaceutical formulation" refers to a preparation that is in a form that allows the biological activity of the active ingredient contained therein to be effective and that does not contain additional components that are unacceptably toxic to the subject to which the formulation is administered.

[0137] A "pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, that is non-toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0138] As used herein, "treatment" (and its grammatical variants, e.g., "treat" or "treating") refers to clinical intervention in an attempt to alter the natural course of the individual being treated, and may be performed either prophylactically or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, prevention of disease onset or recurrence, alleviation of symptoms, attenuation of any direct or indirect pathological consequence of the disease, prevention of metastasis, reduction in the rate of disease progression, remission or palliation of the disease state, and remission or improved prognosis.

[0139] As used herein, the terms "individual," "patient," or "subject" are used interchangeably and refer to any single animal, e.g., mammals (including non-human animals, e.g., dogs, cats, horses, rabbits, zoo animals, cows, pigs, sheep, and non-human primates), for which treatment is desired. In certain embodiments, a patient herein is a human.

[0140] As used herein, "administering" refers to a method of providing a subject (e.g., a patient) with a dosage of an agent or pharmaceutical composition (e.g., a pharmaceutical composition comprising an agent). Administration may be by any suitable means, including parenteral, intrapulmonary, and intranasal, and, if desired, for localized treatment, intralesional administration. Parenteral infusions include, for example, intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. Dosing may be by any suitable route, for example, by injection (e.g., intravenous or subcutaneous injection), depending in part on whether administration is temporary or chronic. Various dosing schedules are contemplated herein, including, but not limited to, single or multiple administrations over various time points, bolus administration, and pulse infusion.

[0141] The term "concurrently" is used herein to refer to the administration of two or more therapeutic agents, where at least a portion of the administration overlaps in time. Thus, concurrent administration includes a dosing regimen in which the administration of one or more agents continues after discontinuing the administration of one or more other agents.

[0142] The term "package insert" is used to refer to instructions customarily included within commercial packaging of a therapeutic product that contain information about the indications, uses, dosages, administration, concomitant therapy, contraindications, and / or warnings regarding the use of such therapeutic product.

[0143] An "article of manufacture" is any article of manufacture (e.g., package or container) or kit that includes at least one reagent, e.g., a medicament for treating a disease or disorder (e.g., cancer) or a reagent for specifically detecting a biomarker described herein (e.g., a kinase fusion described herein, or a fusion nucleic acid molecule or polypeptide). In certain embodiments, the article of manufacture or kit is promoted, distributed, or sold as a unit for performing a method described herein.

[0144] As used herein, the phrase "based on" means that information about one or more biomarkers (e.g., kinase fusions described herein, or fusion nucleic acid molecules or polypeptides) is used to inform treatment decisions, information provided on package inserts, marketing / promotional guidance, etc.

[0145] The terms "allele frequency" and "allele fraction" are used interchangeably herein and refer to the fraction of sequence reads that correspond to a particular allele relative to the total number of sequence reads for a genomic locus. The terms "variant allele frequency" and "variant allele fraction" are used interchangeably herein and refer to the fraction of sequence reads that correspond to a particular variant allele relative to the total number of sequence reads for a genomic locus.

[0146] III. METHODS, SYSTEMS, AND DEVICES In certain embodiments, the present invention provides methods for selecting a treatment for an individual with cancer; methods for identifying one or more treatment options for an individual with cancer; methods for predicting survival of an individual with cancer; methods for treating or delaying the progression of cancer; methods for monitoring, evaluating, or screening an individual with cancer; methods for evaluating an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule, or a fusion polypeptide encoded by a fusion nucleic acid molecule, in cancer in an individual; Provided herein are methods for detecting RBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecules, or fusion polypeptides encoded by the fusion nucleic acid molecules; methods for detecting the presence or absence of cancer in an individual; methods for monitoring the progression or recurrence of cancer in an individual; methods for identifying candidate treatments for cancer in an individual in need thereof; methods for identifying individuals with cancer that may benefit from treatments, including anti-cancer therapies; and methods for predicting survival of individuals with cancer treated with treatments, including anti-cancer therapies.

[0147] In some embodiments, the methods provided herein include detecting an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule, or a fusion polypeptide encoded by the fusion nucleic acid molecule, in a sample from an individual, e.g., an individual with cancer, an individual suspected of having cancer, an individual receiving treatment for cancer, or an individual being tested for cancer. In some embodiments, detection of the fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule in the sample identifies the individual as one who may benefit from an anti-cancer therapy, e.g., a treatment, including those described herein. In some embodiments, the methods include selecting an anti-cancer therapy as a treatment for the individual with cancer, e.g., in response to detection of an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule, or a fusion polypeptide encoded by the fusion nucleic acid molecule in the sample. In some embodiments, the method includes generating a report including one or more treatment options identified for the individual based at least in part on detection of an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule, or a fusion polypeptide encoded by the fusion nucleic acid molecule, in a sample from the individual. In some embodiments, the one or more treatment options include an anti-cancer therapy described herein. In some embodiments, the method includes administering to the individual an effective amount of an anti-cancer therapy, including those described herein, in response to detection of an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule, or a fusion polypeptide encoded by the fusion nucleic acid molecule, in a sample from the individual.In some embodiments, in response to detecting an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule, or a fusion polypeptide encoded by the fusion nucleic acid molecule, in a sample from the individual, the individual is predicted to have a longer survival when treated with an anti-cancer therapy, e.g., a treatment including those described herein, compared to the survival of an individual with a cancer that does not contain the fusion nucleic acid molecule or the fusion polypeptide encoded by the fusion nucleic acid molecule. In some embodiments, the method comprises, for example, providing an assessment of the fusion nucleic acid molecule or the fusion polypeptide encoded by the fusion nucleic acid molecule in response to detecting the presence or absence of an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule, or the fusion polypeptide encoded by the fusion nucleic acid molecule in the sample. In some embodiments, the method comprises detecting the presence or absence of, or obtaining knowledge of the presence or absence of, cancer in a sample from the individual. In some embodiments, the methods comprise detecting the presence or absence of an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule, or a fusion polypeptide encoded by the fusion nucleic acid molecule, in a first sample obtained from the individual at a first time point; detecting the presence or absence of an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule, or a fusion polypeptide encoded by the fusion nucleic acid molecule, in a second sample obtained from the individual at a second time point after the first time point; and providing an assessment of cancer progression or cancer recurrence in the individual based at least in part on the presence or absence of the fusion nucleic acid molecule or the fusion polypeptide encoded by the fusion nucleic acid molecule in the first sample and / or the second sample.In some embodiments, the method includes performing DNA sequencing on a sample obtained from the individual to determine a sequencing mutation profile in the gene, wherein the sequencing mutation profile identifies the presence or absence of an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule. In some embodiments, the method includes identifying a candidate treatment based at least in part on the sequencing mutation profile in the gene. In some embodiments, the candidate treatment comprises an anti-cancer therapy described herein. In some embodiments, the candidate treatment is identified based at least in part on the presence of an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule identified in the sequencing mutation profile.

[0148] In some embodiments, the methods provided herein include obtaining knowledge of an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule, or a fusion polypeptide encoded by the fusion nucleic acid molecule, in a sample from an individual, e.g., an individual who has cancer, an individual suspected of having cancer, an individual receiving treatment for cancer, or an individual being tested for cancer. In some embodiments, knowledge of the presence of an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule, or a fusion polypeptide encoded by the fusion nucleic acid molecule, in a sample from the individual identifies the individual as one who may benefit from an anti-cancer therapy, e.g., a treatment, including those described herein. In some embodiments, the method includes selecting an anti-cancer therapy, e.g., one described herein, as a treatment for an individual with cancer in response to knowledge of the presence of an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule, or a fusion polypeptide encoded by the fusion nucleic acid molecule, in a sample from the individual. In some embodiments, the method includes generating a report including one or more treatment options identified for the individual based at least in part on knowledge of the presence of an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule, or a fusion polypeptide encoded by the fusion nucleic acid molecule, in a sample from the individual. In some embodiments, the one or more treatment options include an anti-cancer therapy described herein. In some embodiments, in response to obtaining knowledge of the presence of an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule, or a fusion polypeptide encoded by the fusion nucleic acid molecule, in a sample from the individual, the individual is classified as a candidate to receive an anti-cancer therapy, e.g., a treatment including those described herein.In some embodiments, in response to obtaining knowledge of the presence of an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule, or a fusion polypeptide encoded by the fusion nucleic acid molecule, in a sample from the individual, the individual is identified as likely to respond to an anti-cancer therapy, e.g., a treatment including those described herein. In some embodiments, in response to obtaining knowledge of the presence of an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule, or a fusion polypeptide encoded by the fusion nucleic acid molecule, in a sample from the individual, the individual is predicted to have longer survival when treated with a treatment including an anti-cancer therapy, e.g., compared to the survival of an individual having a cancer that does not contain the fusion nucleic acid molecule or the fusion polypeptide encoded by the fusion nucleic acid molecule. In some embodiments, in response to obtaining knowledge of the presence of an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule, or a fusion polypeptide encoded by the fusion nucleic acid molecule, in a sample from the individual, the individual is predicted to have longer survival when treated with a treatment comprising an anti-cancer therapy, compared to an individual having a cancer that does not exhibit the fusion nucleic acid molecule or the fusion polypeptide encoded by the fusion nucleic acid molecule. In some embodiments, the method comprises, in response to obtaining knowledge of an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule, or a fusion polypeptide encoded by the fusion nucleic acid molecule, in a sample from the individual, administering to the individual an effective amount of an anti-cancer therapy, such as a treatment including those described herein.In some embodiments, in response to obtaining knowledge of an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule, or a fusion polypeptide encoded by the fusion nucleic acid molecule, in a sample from the individual, the individual is predicted to have an improved response to treatment with an anti-cancer therapy compared to an individual having a cancer that does not contain an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule, or a fusion polypeptide encoded by the fusion nucleic acid molecule. In some embodiments, the method comprises providing an assessment of the fusion nucleic acid molecule or a fusion polypeptide encoded by the fusion nucleic acid molecule, for example, in response to obtaining knowledge of the presence or absence of an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule, or a fusion polypeptide encoded by the fusion nucleic acid molecule, in a sample from the individual. In some embodiments, the method comprises detecting the presence or absence of, or obtaining knowledge of the presence or absence of, cancer in a sample from the individual.

[0149] In another aspect, a system is provided herein. In some embodiments, the system of the present disclosure comprises a memory configured to store one or more program instructions and one or more processors configured to execute the one or more program instructions. In some embodiments, the one or more program instructions, when executed by the one or more processors, are configured to: (a) obtain a plurality of sequence reads of one or more nucleic acid molecules, wherein the one or more nucleic acid molecules are derived from a sample obtained from an individual; (b) analyze the plurality of sequence reads for the presence of an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule; and (c) detect the fusion nucleic acid molecule in the sample based on the analysis. In some embodiments, the sample is from an individual who has cancer, is suspected of having cancer, is receiving treatment for cancer, or is being tested for cancer.

[0150] In another aspect, a non-transitory computer-readable storage medium is provided herein. In some embodiments, the non-transitory computer-readable storage medium of the present disclosure comprises one or more programs executable by one or more computer processors for executing a method. In some embodiments, the method includes: (a) obtaining, using one or more processors, a plurality of sequence reads of one or more nucleic acid molecules, wherein the one or more nucleic acid molecules are derived from a sample obtained from an individual; (b) analyzing, using one or more processors, the plurality of sequence reads for the presence of an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule; and (c) detecting, using the one or more processors, the fusion nucleic acid molecule in the sample based on the analysis. In some embodiments, the sample is from an individual who has cancer, is suspected of having cancer, is receiving treatment for cancer, or is being tested for cancer.

[0151] In some embodiments of any of the methods, systems, or non-transitory computer-readable storage media provided herein, the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1. In some embodiments, the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1, and the ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1 comprises or results from breakpoint 1 and / or breakpoint 2 corresponding to the ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 3. In some embodiments, the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1, and the cancer is carcinoma, sarcoma, lymphoma, leukemia, myeloma, germ cell carcinoma, or blastoma. In some embodiments, the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1, and the cancer is a solid tumor. In some embodiments, the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1, and the cancer is a hematological malignancy.In some embodiments, the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1, and the cancer is B-cell cancer, melanoma, breast cancer, lung cancer, bronchial cancer, colorectal cancer, prostate cancer, pancreatic cancer, stomach cancer, ovarian cancer, urinary bladder cancer, brain cancer, central nervous system cancer, peripheral nervous system cancer, esophageal cancer, cervical cancer, uterine cancer, endometrial cancer, oral cavity cancer, pharyngeal cancer, liver cancer, kidney cancer, testicular cancer, biliary tract cancer, small intestine cancer, appendix cancer, salivary gland cancer, thyroid cancer, or the like. cancer), adrenal cancer, osteosarcoma, chondrosarcoma, cancer of the blood tissue, adenocarcinoma, inflammatory myofibroblastic tumor, gastrointestinal stromal tumor (GIST), colon cancer, multiple myeloma (MM), myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), polycythemia vera, Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL) ), soft tissue sarcoma, fibrosarcoma, myxosarcoma, liposarcoma, osteosarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, medullary carcinoma, bronchogenic lung carcinoma, renal cell carcinoma, hepatocellular carcinoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, bladder cancer carcinoma), epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, retinoblastoma, follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, hepatocellular carcinoma, thyroid cancer, gastric cancer, head and neck cancer, small cell carcinoma, essential thrombocythemia, primary myelofibrosis, hypereosinophilic syndrome, systemic mastocytosis, familial hypereosinophilia, chronic eosinophilic leukemia, neuroendocrine carcinoma, or carcinoid tumor.In some embodiments, the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1, and the cancer is appendix adenocarcinoma, bladder adenocarcinoma, bladder urothelial (transitional cell) carcinoma, not otherwise specified (NOS) breast cancer, NOS breast cancer, carcinoma), invasive ductal carcinoma (IDC), invasive lobular carcinoma of the breast (ILC), cervical squamous cell carcinoma (SCC), colon adenocarcinoma (CRC), esophageal adenocarcinoma, NOS esophageal carcinoma, esophageal squamous cell carcinoma (SCC), intraocular melanoma, gallbladder adenocarcinoma, gastroesophageal junction adenocarcinoma, intrahepatic cholangiocarcinoma, NOS kidney cancer, hepatocellular carcinoma (HCC), NOS lung cancer, lung adenocarcinoma, lung large cell carcinoma, NOS non-small cell lung cancer (NSCLC), lung undifferentiated small cell alveolar carcinoma, lung squamous cell carcinoma (SCC), NOS ovarian cancer, NOS pancreatic cancer, pancreatic ductal adenocarcinoma, pancreaticobiliary carcinoma, NOS prostate cancer, prostatic acinar adenocarcinoma, prostatic ductal adenocarcinoma, rectal adenocarcinoma (CRC), cutaneous melanoma, small intestine adenocarcinoma, NOS soft tissue sarcoma, NOS gastric adenocarcinoma, NOS carcinoma of unknown primary, adenocarcinoma of unknown primary, NOS carcinoma of unknown primary (CUP), neuroendocrine tumor of unknown primary, squamous cell carcinoma (SCC) of unknown primary, or NOS endometrial adenocarcinoma. In some embodiments, the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1, and the cancer is a cancer corresponding to an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 4.In some embodiments, the fusion nucleic acid molecule is an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 1, the cancer is a cancer corresponding to an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 5, and the fusion nucleic acid molecule comprises or results from breakpoint 1 and / or breakpoint 2 corresponding to an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 5.

[0152] In some embodiments of any of the methods, systems, or non-transitory computer-readable storage media provided herein, the fusion nucleic acid molecule is an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2, and the cancer is a cancer corresponding to the ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2. In some embodiments, the fusion nucleic acid molecule is an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2, the cancer is a cancer corresponding to an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 2, and the fusion nucleic acid molecule comprises or results from breakpoint 1 and / or breakpoint 2 corresponding to an ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecule listed in Table 6.

[0153] A. Kinase Fusions Certain aspects of the present disclosure relate to genomic rearrangements involving kinase-encoding genes, such as the ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 genes. The ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 rearrangements of the present disclosure can be associated with any chromosomal translocation, fusion, or rearrangement involving the ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 gene locus. In some embodiments, the rearrangements of the present disclosure result in fusion nucleic acid molecules that include at least a portion of an ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 gene fused to at least a portion of another gene. Accordingly, certain aspects of the present disclosure relate to ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion nucleic acid molecules and ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 fusion polypeptides encoded by such fusion nucleic acid molecules.

[0154] In some aspects, provided herein are rearrangements comprising the ALK gene, and ALK fusion nucleic acid molecules and polypeptides.

[0155] As used herein, "anaplastic lymphoma kinase" or "ALK" refers to a gene encoding an ALK mRNA or polypeptide. The ALK gene encodes the ALK receptor tyrosine kinase protein. ALK is also known as CD246, NBLST3, anaplastic lymphoma receptor tyrosine kinase, and ALK receptor tyrosine kinase. In some embodiments, the ALK gene is a human ALK gene. An exemplary ALK gene is represented by NCBI gene ID number 238. An exemplary ALK mRNA sequence is represented by NCBI reference sequence NM_004304, which is provided below as SEQ ID NO: 1. An exemplary amino acid sequence of an ALK polypeptide is represented by NCBI reference sequence NP_004295.

[0156] In some aspects, provided herein are rearrangements comprising the BRAF gene, and BRAF fusion nucleic acid molecules and polypeptides.

[0157] As used herein, "B-Raf proto-oncogene serine / threonine kinase" or "BRAF" refers to a gene encoding a BRAF mRNA or polypeptide. The BRAF gene encodes the BRAF serine / threonine kinase. BRAF is also known as NS7, B-raf, BRAF1, RAFB1, B-RAF1, and B-Raf proto-oncogene serine / threonine kinase. In some embodiments, the BRAF gene is a human BRAF gene. An exemplary BRAF gene is represented by NCBI Gene ID number 673. An exemplary BRAF mRNA sequence is represented by NCBI Reference Sequence NM_004333, which is provided below as SEQ ID NO: 2. An exemplary amino acid sequence of a BRAF polypeptide is represented by NCBI Reference Sequence NP_004324.

[0158] In some aspects, provided herein are rearrangements comprising the EGFR gene, and EGFR fusion nucleic acid molecules and polypeptides.

[0159] As used herein, "epidermal growth factor receptor" or "EGFR" refers to a gene encoding an EGFR mRNA or polypeptide. The EGFR gene encodes the EGFR receptor tyrosine kinase protein. EGFR is also known as ERBB, ERRP, HER1, mENA, ERBB1, PIG61, NISBD2, epidermal growth factor receptor, and EGFR receptor tyrosine kinase. In some embodiments, the EGFR gene is a human EGFR gene. An exemplary EGFR gene is represented by NCBI Gene ID number 1956. An exemplary EGFR mRNA sequence is represented by NCBI Reference Sequence NM_005228, which is provided below as SEQ ID NO: 3. An exemplary amino acid sequence of an EGFR polypeptide is represented by NCBI Reference Sequence NP_005219.

[0160] In some aspects, provided herein are rearrangements comprising the ERBB2 gene, and ERBB2 fusion nucleic acid molecules and polypeptides.

[0161] As used herein, "erb-b2 receptor tyrosine kinase 2" or "ERBB2" refers to a gene encoding an ERBB2 mRNA or polypeptide. The ERBB2 gene encodes the ERBB2 receptor tyrosine kinase protein. ERBB2 is also known as NEU, NGL, HER2, TKR1, CD340, HER-2, VSCN2, MLN 19, HER-2 / neu, epidermal growth factor, and ERBB2 receptor tyrosine kinase. In some embodiments, the ERBB2 gene is a human ERBB2 gene. An exemplary ERBB2 gene is represented by NCBI Gene ID number 2064. An exemplary ERBB2 mRNA sequence is represented by NCBI Reference Sequence NM_004448, which is provided below as SEQ ID NO: 4. An exemplary amino acid sequence of an ERBB2 polypeptide is represented by NCBI Reference Sequence NP_004439.

[0162] In some aspects, provided herein are rearrangements comprising the FGFR1 gene, and FGFR1 fusion nucleic acid molecules and polypeptides.

[0163] As used herein, "fibroblast growth factor receptor 1" or "FGFR1" refers to a gene encoding an FGFR1 mRNA or polypeptide. The FGFR1 gene encodes the FGFR1 receptor tyrosine kinase protein. FGFR1 is also known as CEK, FLG, HH2, OGD, ECCL, FLT2, KAL2, BFGFR, CD331, FGFBR, FLT-2, HBGFR, N-SAM, FGFR-1, HRTFDS, bFGF-R-1, fibroblast growth factor receptor 1, and FGFR1 receptor tyrosine kinase. In some embodiments, the FGFR1 gene is a human FGFR1 gene. An exemplary FGFR1 gene is represented by NCBI gene ID number 2260. An exemplary FGFR1 mRNA sequence is represented by NCBI reference sequence NM_015850, which is provided below as SEQ ID NO: 5. An exemplary amino acid sequence of an FGFR1 polypeptide is represented by the NCBI reference sequence NP_056934. (SEQ ID NO: 5)

[0164] In some aspects, provided herein are rearrangements comprising the FGFR2 gene, and FGFR2 fusion nucleic acid molecules and polypeptides.

[0165] As used herein, "fibroblast growth factor receptor 2" or "FGFR2" refers to a gene encoding an FGFR2 mRNA or polypeptide. The FGFR2 gene encodes the FGFR2 receptor tyrosine kinase protein. FGFR2 is also known as BBDS, BEK, BFR-1, CD332, CEK3, CFD1, ECT1, JWS, K-SAM, KGFR, TK14, TK25, fibroblast growth factor receptor 2, and FGFR2 receptor tyrosine kinase. In some embodiments, the FGFR2 gene is a human FGFR2 gene. An exemplary FGFR2 gene is represented by NCBI Gene ID number 2263. An exemplary FGFR2 mRNA sequence is represented by NCBI Reference Sequence NM_000141, which is provided below as SEQ ID NO: 6. An exemplary amino acid sequence of an FGFR2 polypeptide is represented by NCBI Reference Sequence NP_000132.

[0166] In some aspects, provided herein are rearrangements comprising the FGFR3 gene, and FGFR3 fusion nucleic acid molecules and polypeptides.

[0167] As used herein, "fibroblast growth factor receptor 3" or "FGFR3" refers to a gene encoding an FGFR3 mRNA or polypeptide. The FGFR3 gene encodes the FGFR3 receptor tyrosine kinase protein. FGFR3 is also known as ACH, CEK2, JTK4, CD333, HSFGFR3EX, fibroblast growth factor receptor 3, and FGFR3 receptor tyrosine kinase. In some embodiments, the FGFR3 gene is a human FGFR3 gene. An exemplary FGFR3 gene is represented by NCBI Gene ID number 2261. An exemplary FGFR3 mRNA sequence is represented by NCBI Reference Sequence NM_000142, which is provided below as SEQ ID NO: 7. An exemplary amino acid sequence of an FGFR3 polypeptide is represented by NCBI Reference Sequence NP_000133.

[0168] In some aspects, provided herein are rearrangements comprising the MET gene, and MET fusion nucleic acid molecules and polypeptides.

[0169] As used herein, "mesenchymal-epithelial transition" or "MET" refers to a gene encoding a MET mRNA or polypeptide. The MET gene encodes the MET receptor tyrosine kinase protein. MET is also known as HGFR, AUTS9, RCCP2, c-Met, DFNB97, mesenchymal-epithelial transition, and MET receptor tyrosine kinase. In some embodiments, the MET gene is a human MET gene. An exemplary MET gene is represented by NCBI Gene ID number 4233. An exemplary MET mRNA sequence is represented by NCBI Reference Sequence NM_000245, which is provided below as SEQ ID NO: 8. An exemplary amino acid sequence of a MET polypeptide is represented by NCBI Reference Sequence NP_000236.

[0170] In some aspects, provided herein are rearrangements comprising the NTRK1 gene, and NTRK1 fusion nucleic acid molecules and polypeptides.

[0171] As used herein, "neurotrophic receptor tyrosine kinase 1" or "NTRK1" refers to a gene encoding an NTRK1 mRNA or polypeptide. The NTRK1 gene encodes the NTRK1 tyrosine kinase protein. NTRK1 is also known as MTC, TRK, TRK1, TRKA, Trk-A, p140-TrkA, and neurotrophic receptor tyrosine kinase 1. In some embodiments, the NTRK1 gene is a human NTRK1 gene. An exemplary NTRK1 gene is represented by NCBI Gene ID number 4914. An exemplary NTRK1 mRNA sequence is represented by NCBI Reference Sequence NM_002529, which is provided below as SEQ ID NO: 12. An exemplary amino acid sequence of an NTRK1 polypeptide is represented by NCBI Reference Sequence NP_002520.

[0172] In some aspects, provided herein are rearrangements comprising the RAF1 gene, and RAF1 fusion nucleic acid molecules and polypeptides.

[0173] As used herein, "rapidly accelerating fibrosarcoma" or "RAF1" refers to a gene encoding a RAF1 mRNA or polypeptide. The RAF1 gene encodes the RAF1 serine / threonine kinase. RAF1 is also known as NS5, CRAF, Raf-1, c-Raf, CMD1NN, and rapidly accelerating fibrosarcoma. In some embodiments, the RAF1 gene is a human RAF1 gene. An exemplary RAF1 gene is represented by NCBI Gene ID number 5894. An exemplary RAF1 mRNA sequence is represented by NCBI Reference Sequence NM_002880, which is provided below as SEQ ID NO:9. An exemplary amino acid sequence of a RAF1 polypeptide is represented by NCBI Reference Sequence NP_002871.

[0174] In some aspects, provided herein are rearrangements comprising the RET gene, as well as RET fusion nucleic acid molecules and polypeptides.

[0175] As used herein, "transfection-rearranged" or "RET" refers to a gene encoding a RET mRNA or polypeptide. The RET gene encodes the RET receptor tyrosine kinase protein. RET is also known as PTC, MTC1, HSCR1, MEN2A, MEN2B, CDHF12, CDHR16, RET-ELE1, transfection-rearranged, and RET receptor tyrosine kinase. In some embodiments, the RET gene is a human RET gene. An exemplary RET gene is represented by NCBI Gene ID number 5979. An exemplary RET mRNA sequence is represented by NCBI Reference Sequence NM_020630, which is provided below as SEQ ID NO: 10. An exemplary amino acid sequence of a RET polypeptide is represented by NCBI Reference Sequence NP_065681.

[0176] In some aspects, provided herein are rearrangements comprising the ROS1 gene, as well as ROS1 fusion nucleic acid molecules and polypeptides.

[0177] As used herein, "c-ros oncogene 1" or "ROS1" refers to a gene encoding a ROS1 mRNA or polypeptide. The ROS1 gene encodes the ROS1 receptor tyrosine kinase protein. ROS1 is also known as ROS, MCF3, c-ros-1, c-ros oncogene 1, and ROS1 receptor tyrosine kinase. In some embodiments, the ROS1 gene is a human ROS1 gene. An exemplary ROS1 gene is represented by NCBI Gene ID number 6098. An exemplary ROS1 mRNA sequence is represented by NCBI Reference Sequence NM_002944, which is provided below as SEQ ID NO: 11. An exemplary amino acid sequence of a ROS1 polypeptide is represented by NCBI Reference Sequence NP_002935. (i) kinase-fused nucleic acid molecule

[0178] In some embodiments, the ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 rearrangement results in a gene fusion, which results in a fusion nucleic acid molecule comprising at least a portion of the ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, RET, or ROS1 gene and at least a portion of another gene.

[0179] In some aspects, provided herein are ALK fusion nucleic acid molecules comprising at least a portion of ALK and at least a portion of another gene.

[0180] In some embodiments, an ALK fusion nucleic acid molecule of the disclosure comprises at least a portion of ALK and at least a portion of AGAP1, ARHGEF7, BRE, EPS8, GPR113, HDAC9, MIPOL1, PELI1, SLC39A10, VKORC1L1, PLEKHA7, SPINK5, GCC2, HIP1, KANK1, KLC1, PPFIBP1, SORBS1, TFG, or TPM3. For example, in some embodiments, the ALK fusion nucleic acid molecule is selected from AGAP1-ALK, ARHGEF7-ALK, BRE-ALK, EPS8-ALK, GPR113-ALK, HDAC9-ALK, MIPOL1-ALK, PELI1-ALK, SLC39A10-ALK, VKORC1L1-ALK, ALK-SORBS1, ALK-SPINK5, GCC2-ALK, HIP1-ALK, KANK1-ALK, PLEKHA7-ALK, KLC1-ALK, TFG-ALK, TPM3-ALK, or PPFIBP1-ALK, with the order of the genes being from 5' to 3'. Exemplary, non-limiting ALK fusion nucleic acid molecules are described herein, and / or in any of Tables 1-6, and / or in the Examples herein.

[0181] As used herein, "AGAP1" refers to a gene encoding AGAP1 mRNA or polypeptide. The AGAP1 gene encodes Arf-GAP having GTPase, ANK repeat, and PH domain-containing protein 1. AGAP1 is also known as CENTG2 and KIAA1099. In some embodiments, the AGAP1 gene is a human AGAP1 gene. An exemplary AGAP1 gene is represented by NCBI gene ID number 116987. An exemplary AGAP1 mRNA sequence is represented by NCBI reference sequence NM_014914. An exemplary amino acid sequence of an AGAP1 polypeptide is represented by NCBI reference sequence NP_055729.

[0182] As used herein, "ARHGEF7" refers to a gene encoding ARHGEF7 mRNA or polypeptide. The ARHGEF7 gene encodes the Rho guanine nucleotide exchange factor 7 protein. ARHGEF7 is also known as P50, P85, PAK3, PIXB, COOL1, P50BP, COOL-1, P85SPR, BETA-PIX, P85COOL1, and Nbla10314. In some embodiments, the ARHGEF7 gene is a human ARHGEF7 gene. An exemplary ARHGEF7 gene is represented by NCBI Gene ID number 8874. An exemplary ARHGEF7 mRNA sequence is represented by NCBI Reference Sequence NM_145735. An exemplary amino acid sequence of an ARHGEF7 polypeptide is represented by NCBI Reference Sequence NP_663788.

[0183] As used herein, "BRE" refers to a gene encoding a BRE mRNA or polypeptide. The BRE gene encodes a brain- and reproductive organ-expressed protein. BRE is also known as BABAM2, BRCC4, and BRCC45. In some embodiments, the BRE gene is a human BRE gene. An exemplary BRE gene is represented by NCBI Gene ID number 9577. An exemplary BRE mRNA sequence is represented by NCBI Reference Sequence NM_004899. An exemplary amino acid sequence of a BRE polypeptide is represented by NCBI Reference Sequence NP_004890.

[0184] As used herein, "EPS8" refers to a gene encoding an EPS8 mRNA or polypeptide. The EPS8 gene encodes the epidermal growth factor receptor pathway substrate 8 protein. EPS8 is also known as DFNB102. In some embodiments, the EPS8 gene is a human EPS8 gene. An exemplary EPS8 gene is represented by NCBI Gene ID number 2059. An exemplary EPS8 mRNA sequence is represented by NCBI Reference Sequence NM_004447. An exemplary amino acid sequence of an EPS8 polypeptide is represented by NCBI Reference Sequence NP_004438.

[0185] As used herein, "GPR113" refers to a gene encoding a GPR113 mRNA or polypeptide. The GPR113 gene encodes a G protein-coupled receptor 113 protein. GPR113 is also known as ADGRF3 and PGR23. In some embodiments, the GPR113 gene is a human GPR113 gene. An exemplary GPR113 gene is represented by NCBI gene ID number 165082. An exemplary GPR113 mRNA sequence is represented by NCBI reference sequence NM_153835. An exemplary amino acid sequence of a GPR113 polypeptide is represented by NCBI reference sequence NP_722577.

[0186] As used herein, "HDAC9" refers to a gene encoding HDAC9 mRNA or polypeptide. The HDAC9 gene encodes the histone deacetylase 9 protein. HDAC9 is also known as HD7, HD9, HD7b, HDAC, HDRP, MITR, HDAC7, HDAC7B, HDAC9B, and HDAC9FL. In some embodiments, the HDAC9 gene is a human HDAC9 gene. An exemplary HDAC9 gene is represented by NCBI gene ID number 9734. An exemplary HDAC9 mRNA sequence is represented by NCBI reference sequence NM_058176. An exemplary amino acid sequence of an HDAC9 polypeptide is represented by NCBI reference sequence NP_478056.

[0187] As used herein, "MIPOL1" refers to a gene encoding MIPOL1 mRNA or polypeptide. The MIPOL1 gene encodes the mirror image polydactyly 1 protein. MIPOL1 is also known as CCDC193. In some embodiments, the MIPOL1 gene is a human MIPOL1 gene. An exemplary MIPOL1 gene is represented by NCBI Gene ID number 145282. An exemplary MIPOL1 mRNA sequence is represented by NCBI Reference Sequence NM_138731. An exemplary amino acid sequence of a MIPOL1 polypeptide is represented by NCBI Reference Sequence NP_620059.

[0188] As used herein, "PELI1" refers to a gene encoding a PELI1 mRNA or polypeptide. The PELI1 gene encodes the mirror image polydactyly 1 protein. In some embodiments, the PELI1 gene is a human PELI1 gene. An exemplary PELI1 gene is represented by NCBI Gene ID number 57162. An exemplary PELI1 mRNA sequence is represented by NCBI Reference Sequence NM_020651. An exemplary amino acid sequence of a PELI1 polypeptide is represented by NCBI Reference Sequence NP_065702.

[0189] As used herein, "SLC39A10" refers to a gene encoding SLC39A10 mRNA or polypeptide. The SLC39A10 gene encodes a solute transporter family 39 member 10 protein. SLC39A10 is also known as LZT-Hs2. In some embodiments, the SLC39A10 gene is a human SLC39A10 gene. An exemplary SLC39A10 gene is represented by NCBI gene ID number 57181. An exemplary SLC39A10 mRNA sequence is represented by NCBI reference sequence NM_020342. An exemplary amino acid sequence of a SLC39A10 polypeptide is represented by NCBI reference sequence NP_065075.

[0190] As used herein, "VKORC1L1" refers to a gene encoding VKORC1L1 mRNA or polypeptide. The VKORC1L1 gene encodes a Vitamin K epoxide reductase complex subunit 1-like 1 protein. In some embodiments, the VKORC1L1 gene is a human VKORC1L1 gene. An exemplary VKORC1L1 gene is represented by NCBI gene ID number 154807. An exemplary VKORC1L1 mRNA sequence is represented by NCBI reference sequence NM_173517. An exemplary amino acid sequence of a VKORC1L1 polypeptide is represented by NCBI reference sequence NP_775788.

[0191] As used herein, "SORBS1" refers to a gene encoding a SORBS1 mRNA or polypeptide. The SORBS1 gene encodes sorbin and SH3 domain-containing 1 protein. SORBS1 is also known as CAP, FLAF2, R85FL, SH3D5, SORB1, and SH3P12. In some embodiments, the SORBS1 gene is a human SORBS1 gene. An exemplary SORBS1 gene is represented by NCBI Gene ID number 10580. An exemplary SORBS1 mRNA sequence is represented by NCBI Reference Sequence NM_006434. An exemplary amino acid sequence of a SORBS1 polypeptide is represented by NCBI Reference Sequence NP_006425.

[0192] As used herein, "SPINK5" refers to a gene encoding SPINK5 mRNA or polypeptide. The SPINK5 gene encodes the serine peptidase inhibitor Kazal type 5 protein. SPINK5 is also known as NS, NETS, LEKTI, LETKI, and VAKTI. In some embodiments, the SPINK5 gene is a human SPINK5 gene. An exemplary SPINK5 gene is represented by NCBI Gene ID number 11005. An exemplary SPINK5 mRNA sequence is represented by NCBI Reference Sequence NM_006846. An exemplary amino acid sequence of a SPINK5 polypeptide is represented by NCBI Reference Sequence NP_006837.

[0193] As used herein, "GCC2" refers to a gene encoding GCC2 mRNA or polypeptide. The GCC2 gene encodes a GRIP and coiled-coil domain-containing 2 protein. GCC2 is also known as REN53, GCC185, and RANBP2L4. In some embodiments, the GCC2 gene is a human GCC2 gene. An exemplary GCC2 gene is represented by NCBI gene ID number 9648. An exemplary GCC2 mRNA sequence is represented by NCBI reference sequence NM_181453. An exemplary amino acid sequence of a GCC2 polypeptide is represented by NCBI reference sequence NP_852118.

[0194] As used herein, "HIP1" refers to a gene encoding HIP1 mRNA or polypeptide. The HIP1 gene encodes the huntingtin-interacting protein 1 protein. HIP1 is also known as SHON, HIP-I, ILWEQ, SHON beta, and SHON gamma. In some embodiments, the HIP1 gene is a human HIP1 gene. An exemplary HIP1 gene is represented by NCBI Gene ID number 3092. An exemplary HIP1 mRNA sequence is represented by NCBI Reference Sequence NM_005338. An exemplary amino acid sequence of a HIP1 polypeptide is represented by NCBI Reference Sequence NP_005329.

[0195] As used herein, "KANK1" refers to a gene encoding KANK1 mRNA or polypeptide. The KANK1 gene encodes a KN motif and ankyrin repeat domain 1 protein. KANK1 is also known as KANK, CPSQ2, and ANKRD15. In some embodiments, the KANK1 gene is a human KANK1 gene. An exemplary KANK1 gene is represented by NCBI gene ID number 23189. An exemplary KANK1 mRNA sequence is represented by NCBI reference sequence NM_015158. An exemplary amino acid sequence of a KANK1 polypeptide is represented by NCBI reference sequence NP_055973.

[0196] As used herein, "PLEKHA7" refers to a gene encoding a PLEKHA7 mRNA or polypeptide. The PLEKHA7 gene encodes a pleckstrin homology domain-containing A7 protein. PLEKHA7 is also known as DKFZp686M22243. In some embodiments, the PLEKHA7 gene is a human PLEKHA7 gene. An exemplary PLEKHA7 gene is represented by NCBI Gene ID number 144100. An exemplary PLEKHA7 mRNA sequence is represented by NCBI Reference Sequence NM_001329630. An exemplary amino acid sequence of a PLEKHA7 polypeptide is represented by NCBI Reference Sequence NP_001316559.

[0197] As used herein, "KLC1" refers to a gene encoding KLC1 mRNA or polypeptide. The KLC1 gene encodes the kinesin light chain 1 protein. KLC1 is also known as KLC, KNS2, and KNS2A. In some embodiments, the KLC1 gene is a human KLC1 gene. An exemplary KLC1 gene is represented by NCBI Gene ID number 3831. An exemplary KLC1 mRNA sequence is represented by NCBI Reference Sequence NM_005552. An exemplary amino acid sequence of a KLC1 polypeptide is represented by NCBI Reference Sequence NP_005543.

[0198] As used herein, "TFG" refers to a gene encoding a TFG mRNA or polypeptide. The TFG gene encodes an ER-to-Golgi transport regulatory protein. TFG is also known as TF6, HMSNP, SPG57, and TRKT3. In some embodiments, the TFG gene is a human TFG gene. An exemplary TFG gene is represented by NCBI gene ID number 10342. An exemplary TFG mRNA sequence is represented by NCBI reference sequence NM_006070. An exemplary amino acid sequence of a TFG polypeptide is represented by NCBI reference sequence NP_006061.

[0199] As used herein, "TPM3" refers to a gene encoding a TPM3 mRNA or polypeptide. The TPM3 gene encodes the tropomyosin 3 protein. TPM3 is also known as TM3, TM5, TRK, CFTD, NEM1, TM-5, TM30, CAPM1, TM30nm, TPM3nu, TPMsk3, hscp30, HEL-189, HEL-S-82p, and OK / SW-cl.5. In some embodiments, the TPM3 gene is a human TPM3 gene. An exemplary TPM3 gene is represented by NCBI Gene ID number 7170. An exemplary TPM3 mRNA sequence is represented by NCBI Reference Sequence NM_152263. An exemplary amino acid sequence of a TPM3 polypeptide is represented by NCBI Reference Sequence NP_689476.

[0200] As used herein, "PPFIBP1" refers to a gene encoding PPFIBP1 mRNA or polypeptide. The PPFIBP1 gene encodes PPFIA-binding protein 1 protein. PPFIBP1 is also known as L2, SGT2, hSGT2, and hSgt2p. In some embodiments, the PPFIBP1 gene is a human PPFIBP1 gene. An exemplary PPFIBP1 gene is represented by NCBI gene ID number 8496. An exemplary PPFIBP1 mRNA sequence is represented by NCBI reference sequence NM_003622. An exemplary amino acid sequence of a PPFIBP1 polypeptide is represented by NCBI reference sequence NP_003613.

[0201] In some aspects, provided herein are BRAF fusion nucleic acid molecules comprising at least a portion of BRAF and at least a portion of another gene.

[0202] In some embodiments, the BRAF fusion nucleic acid molecule comprises at least a portion of BRAF and at least a portion of CCDC88C, COBLL1, CREB3L2, DLC1, GOLGA3, MSI2, TNS3, DOCK4, RAD51, AKAP9, ARMC10, DENND2A, JHDM1D, KIAA1549, MKRN1, NRF1, SLC45A3, SND1, ZC3HAV1, ZNF277, or TRIM24. For example, in some embodiments, the BRAF fusion nucleic acid molecule is selected from CCDC88C-BRAF, COBLL1-BRAF, CREB3L2-BRAF, DLC1-BRAF, GOLGA3-BRAF, MSI2-BRAF, TNS3-BRAF, BRAF-DOCK4, BRAF-RAD51, AKAP9-BRAF, ARMC10-BRAF, DENND2A-BRAF, JHDM1D-BRAF, KIAA1549-BRAF, MKRN1-BRAF, NRF1-BRAF, SLC45A3-BRAF, SND1-BRAF, BRAF-TRIM24, ZC3HAV1-BRAF, or ZNF277-BRAF, with the order of genes being from 5' to 3'. Exemplary, non-limiting BRAF fusion nucleic acid molecules are described herein, and / or in any of Tables 1-6, and / or in the Examples herein.

[0203] As used herein, "CCDC88C" refers to a gene encoding a CCDC88C mRNA or polypeptide. The CCDC88C gene encodes a coiled-coil domain-containing 88C protein. CCDC88C is also known as HYC1, DAPLE, HKRP2, SCA40, and KIAA1509. In some embodiments, the CCDC88C gene is a human CCDC88C gene. An exemplary CCDC88C gene is represented by NCBI gene ID number 440193. An exemplary CCDC88C mRNA sequence is represented by NCBI reference sequence NM_001080414. An exemplary amino acid sequence of a CCDC88C polypeptide is represented by NCBI reference sequence NP_001073883.

[0204] As used herein, "COBLL1" refers to a gene encoding COBLL1 mRNA or polypeptide. The COBLL1 gene encodes the Cordon Bleu WH2 repeat protein-like 1 protein. COBLL1 is also known as COBLR1 and KIAA0977. In some embodiments, the COBLL1 gene is a human COBLL1 gene. An exemplary COBLL1 gene is represented by NCBI Gene ID number 22837. An exemplary COBLL1 mRNA sequence is represented by NCBI Reference Sequence NM_014900. An exemplary amino acid sequence of the COBLL1 polypeptide is represented by NCBI Reference Sequence NP_055715.

[0205] As used herein, "CREB3L2" refers to a gene encoding a CREB3L2 mRNA or polypeptide. The CREB3L2 gene encodes a cAMP response element binding protein 3-like 2 protein. CREB3L2 is also known as BBF2H7 and TCAG_1951439. In some embodiments, the CREB3L2 gene is a human CREB3L2 gene. An exemplary CREB3L2 gene is represented by NCBI gene ID number 64764. An exemplary CREB3L2 mRNA sequence is represented by NCBI reference sequence NM_194071. An exemplary amino acid sequence of a CREB3L2 polypeptide is represented by NCBI reference sequence NP_919047.

[0206] As used herein, "DLC1" refers to a gene encoding DLC1 mRNA or polypeptide. The DLC1 gene encodes the DLC1 RhoGTPase-activating protein. DLC1 is also known as HP, ARHGAP7, STARD12, and p122-RhoGAP. In some embodiments, the DLC1 gene is a human DLC1 gene. An exemplary DLC1 gene is represented by NCBI Gene ID number 10395. An exemplary DLC1 mRNA sequence is represented by NCBI Reference Sequence NM_024767. An exemplary amino acid sequence of a DLC1 polypeptide is represented by NCBI Reference Sequence NP_079043.

[0207] As used herein, "GOLGA3" refers to a gene encoding GOLGA3 mRNA or polypeptide. The GOLGA3 gene encodes the Golgin A3 protein. GOLGA3 is also known as MEA-2 and GCP170. In some embodiments, the GOLGA3 gene is a human GOLGA3 gene. An exemplary GOLGA3 gene is represented by NCBI Gene ID number 2802. An exemplary GOLGA3 mRNA sequence is represented by NCBI Reference Sequence NM_005895. An exemplary amino acid sequence of a GOLGA3 polypeptide is represented by NCBI Reference Sequence NP_005886.

[0208] As used herein, "MSI2" refers to a gene encoding MSI2 mRNA or polypeptide. The MSI2 gene encodes the musashi RNA-binding protein 2 protein. MSI2 is also known as MSI2H. In some embodiments, the MSI2 gene is a human MSI2 gene. An exemplary MSI2 gene is represented by NCBI gene ID number 124540. An exemplary MSI2 mRNA sequence is represented by NCBI reference sequence NM_138962. An exemplary amino acid sequence of the MSI2 polypeptide is represented by NCBI reference sequence NP_620412.

[0209] As used herein, "TNS3" refers to a gene encoding a TNS3 mRNA or polypeptide. The TNS3 gene encodes the tensin 3 protein. TNS3 is also known as TEM6, H_NH0549I23.2, FLJ13732, and TENS1. In some embodiments, the TNS3 gene is a human TNS3 gene. An exemplary TNS3 gene is represented by NCBI gene ID number 64759. An exemplary TNS3 mRNA sequence is represented by NCBI reference sequence NM_022748. An exemplary amino acid sequence of a TNS3 polypeptide is represented by NCBI reference sequence NP_073585.

[0210] As used herein, "DOCK4" refers to a gene encoding a DOCK4 mRNA or polypeptide. The DOCK4 gene encodes cytokinesis dedicator 4 protein. DOCK4 is also known as FLJ34238 and KIAA0716. In some embodiments, the DOCK4 gene is a human DOCK4 gene. An exemplary DOCK4 gene is represented by NCBI Gene ID number 9732. An exemplary DOCK4 mRNA sequence is represented by NCBI Reference Sequence NM_014705. An exemplary amino acid sequence of a DOCK4 polypeptide is represented by NCBI Reference Sequence NP_055520.

[0211] As used herein, "RAD51" refers to a gene encoding a RAD51 mRNA or polypeptide. The RAD51 gene encodes the RAD51 recombinase protein. RAD51 is also known as RECA, BRCC5, FANCR, MRMV2, HRAD51, RAD51A, HsRad51, and HsT16930. In some embodiments, the RAD51 gene is a human RAD51 gene. An exemplary RAD51 gene is represented by NCBI Gene ID number 5888. An exemplary RAD51 mRNA sequence is represented by NCBI Reference Sequence NM_002875. An exemplary amino acid sequence of a RAD51 polypeptide is represented by NCBI Reference Sequence NP_002866.

[0212] As used herein, "AKAP9" refers to a gene encoding AKAP9 mRNA or polypeptide. The AKAP9 gene encodes the A-kinase anchor protein 9 protein. AKAP9 is also known as LQT11, PRKA9, AKAP-9, CG-NAP, YOTIAO, AKAP350, AKAP450, PPP1R45, HYPERION, and MU-RMS-40.16A. In some embodiments, the AKAP9 gene is a human AKAP9 gene. An exemplary AKAP9 gene is represented by NCBI gene ID number 10142. An exemplary AKAP9 mRNA sequence is represented by NCBI reference sequence NM_005751. An exemplary amino acid sequence of an AKAP9 polypeptide is represented by NCBI reference sequence NP_005742.

[0213] As used herein, "ARMC10" refers to a gene encoding ARMC10 mRNA or polypeptide. The ARMC10 gene encodes the armadillo repeat-containing 10 protein. ARMC10 is also known as SVH, PNAS112, PNAS-112, and PSEC0198. In some embodiments, the ARMC10 gene is a human ARMC10 gene. An exemplary ARMC10 gene is represented by NCBI gene ID number 83787. An exemplary ARMC10 mRNA sequence is represented by NCBI reference sequence NM_031905. An exemplary amino acid sequence of an ARMC10 polypeptide is represented by NCBI reference sequence NP_114111.

[0214] As used herein, "DENND2A" refers to a gene encoding a DENND2A mRNA or polypeptide. The DENND2A gene encodes a DENN domain-containing 2A protein. DENND2A is also known as FAM31D and KIAA1277. In some embodiments, the DENND2A gene is a human DENND2A gene. An exemplary DENND2A gene is represented by NCBI gene ID number 27147. An exemplary DENND2A mRNA sequence is represented by NCBI reference sequence NM_015689. An exemplary amino acid sequence of a DENND2A polypeptide is represented by NCBI reference sequence NP_056504.

[0215] As used herein, "JHDM1D" refers to a gene encoding a JHDM1D mRNA or polypeptide. The JHDM1D gene encodes a Jumonji C domain-containing histone demethylase 1 homolog D protein. JHDM1D is also known as KDM7A. In some embodiments, the JHDM1D gene is a human JHDM1D gene. An exemplary JHDM1D gene is represented by NCBI Gene ID number 80853. An exemplary JHDM1D mRNA sequence is represented by NCBI Reference Sequence NM_030647. An exemplary amino acid sequence of a JHDM1D polypeptide is represented by NCBI Reference Sequence NP_085150.

[0216] As used herein, "KIAA1549" refers to a gene encoding KIAA1549 mRNA or polypeptide. The KIAA1549 gene encodes the KIAA1549 protein. KIAA1549 is also known as RP86. In some embodiments, the KIAA1549 gene is a human KIAA1549 gene. An exemplary KIAA1549 gene is represented by NCBI gene ID number 57670. An exemplary KIAA1549 mRNA sequence is represented by NCBI reference sequence NM_020910. An exemplary amino acid sequence of a KIAA1549 polypeptide is represented by NCBI reference sequence NP_065961.

[0217] As used herein, "MKRN1" refers to a gene encoding MKRN1 mRNA or polypeptide. The MKRN1 gene encodes the makorin ring finger protein 1 protein. MKRN1 is also known as RNF61. In some embodiments, the MKRN1 gene is a human MKRN1 gene. An exemplary MKRN1 gene is represented by NCBI gene ID number 23608. An exemplary MKRN1 mRNA sequence is represented by NCBI reference sequence NM_013446. An exemplary amino acid sequence of an MKRN1 polypeptide is represented by NCBI reference sequence NP_038474.

[0218] As used herein, "NRF1" refers to a gene encoding NRF1 mRNA or polypeptide. The NRF1 gene encodes the nuclear respiratory factor 1 protein. NRF1 is also known as ALPHA-PAL and EWG. In some embodiments, the NRF1 gene is a human NRF1 gene. An exemplary NRF1 gene is represented by NCBI gene ID number 4899. An exemplary NRF1 mRNA sequence is represented by NCBI reference sequence NM_005011. An exemplary amino acid sequence of an NRF1 polypeptide is represented by NCBI reference sequence NP_005002.

[0219] As used herein, "SLC45A3" refers to a gene encoding SLC45A3 mRNA or polypeptide. The SLC45A3 gene encodes a solute carrier family 45 member 3 protein. SLC45A3 is also known as PRST, IPCA6, IPCA-2, IPCA-6, IPCA-8, PCANAP2, PCANAP6, and PCANAP8. In some embodiments, the SLC45A3 gene is a human SLC45A3 gene. An exemplary SLC45A3 gene is represented by NCBI gene ID number 85414. An exemplary SLC45A3 mRNA sequence is represented by NCBI reference sequence NM_033102. An exemplary amino acid sequence of an SLC45A3 polypeptide is represented by NCBI reference sequence NP_149093.

[0220] As used herein, "SND1" refers to a gene encoding SND1 mRNA or polypeptide. The SND1 gene encodes the staphylococcal nuclease and Tudor domain-containing 1 protein. SND1 is also known as p100, TDRD11, p100 EBNA2 coactivator, and Tudor-SN. In some embodiments, the SND1 gene is a human SND1 gene. An exemplary SND1 gene is represented by NCBI gene ID number 27044. An exemplary SND1 mRNA sequence is represented by NCBI reference sequence NM_014390. An exemplary amino acid sequence of an SND1 polypeptide is represented by NCBI reference sequence NP_055205.

[0221] As used herein, "TRIM24" refers to a gene encoding a TRIM24 mRNA or polypeptide. The TRIM24 gene encodes a tripartite motif-containing 24 protein. TRIM24 is also known as PTC6, TF1A, TIF1, RNF82, TIF1A, hTIF1, and TIF1ALPHA. In some embodiments, the TRIM24 gene is a human TRIM24 gene. An exemplary TRIM24 gene is represented by NCBI Gene ID number 8805. An exemplary TRIM24 mRNA sequence is represented by NCBI Reference Sequence NM_003852. An exemplary amino acid sequence of a TRIM24 polypeptide is represented by NCBI Reference Sequence NP_003843.

[0222] As used herein, "ZC3HAV1" refers to a gene encoding ZC3HAV1 mRNA or polypeptide. The ZC3HAV1 gene encodes the zinc finger CCCH-type-containing antiviral 1 protein. ZC3HAV1 is also known as ZAP, ZC3H2, ARTD13, PARP13, FLB6421, and ZC3HDC2. In some embodiments, the ZC3HAV1 gene is a human ZC3HAV1 gene. An exemplary ZC3HAV1 gene is represented by NCBI gene ID number 56829. An exemplary ZC3HAV1 mRNA sequence is represented by NCBI reference sequence NM_020119. An exemplary amino acid sequence of the ZC3HAV1 polypeptide is represented by NCBI reference sequence NP_064504.

[0223] As used herein, "ZNF277" refers to a gene encoding ZNF277 mRNA or polypeptide. The ZNF277 gene encodes the zinc finger protein 277 protein. ZNF277 is also known as NRIF4 and ZNF277P. In some embodiments, the ZNF277 gene is a human ZNF277 gene. An exemplary ZNF277 gene is represented by NCBI gene ID number 11179. An exemplary ZNF277 mRNA sequence is represented by NCBI reference sequence NM_021994. An exemplary amino acid sequence of a ZNF277 polypeptide is represented by NCBI reference sequence NP_068834.

[0224] In some aspects, provided herein are EGFR fusion nucleic acid molecules comprising at least a portion of EGFR and at least a portion of another gene.

[0225] In some embodiments, an EGFR fusion nucleic acid molecule comprises at least a portion of EGFR and at least a portion of ABCB1, PDE7A, EZH2, FLJ45974, or ZNF479. For example, in some embodiments, the EGFR fusion nucleic acid molecule is selected from ABCB1-EGFR, PDE7A-EGFR, EGFR-EZH2, EGFR-FLJ45974, or EGFR-ZNF479, where the gene order is from 5' to 3'. Exemplary, non-limiting EGFR fusion nucleic acid molecules are described herein and / or in Tables 1 and 3-5 and / or in the Examples herein.

[0226] As used herein, "ABCB1" refers to a gene encoding ABCB1 mRNA or polypeptide. The ABCB1 gene encodes the ATP-binding cassette subfamily B member 17 protein. ABCB1 is also known as CLCS, MDR1, P-GP, PGY1, ABC20, CD243, GP170, and p-170. In some embodiments, the ABCB1 gene is a human ABCB1 gene. An exemplary ABCB1 gene is represented by NCBI Gene ID number 5243. An exemplary ABCB1 mRNA sequence is represented by NCBI Reference Sequence NM_000927. An exemplary amino acid sequence of an ABCB1 polypeptide is represented by NCBI Reference Sequence NP_000918.

[0227] As used herein, "PDE7A" refers to a gene encoding a PDE7A mRNA or polypeptide. The PDE7A gene encodes a phosphodiesterase 7A protein. PDE7A is also known as HCP1 and PDE7. In some embodiments, the PDE7A gene is a human PDE7A gene. An exemplary PDE7A gene is represented by NCBI gene ID number 5150. An exemplary PDE7A mRNA sequence is represented by NCBI reference sequence NM_002603. An exemplary amino acid sequence of a PDE7A polypeptide is represented by NCBI reference sequence NP_002594.

[0228] As used herein, "EZH2" refers to a gene encoding EZH2 mRNA or polypeptide. The EZH2 gene encodes an enhancer protein of the zeste 2 polycomb repressive complex 2 subunit. EZH2 is also known as EZH1, WVS, ENX1, KMT6, WVS2, ENX-1, EZH2b, and KMT6A. In some embodiments, the EZH2 gene is a human EZH2 gene. An exemplary EZH2 gene is represented by NCBI gene ID number 2146. An exemplary EZH2 mRNA sequence is represented by NCBI reference sequence NM_004456. An exemplary amino acid sequence of an EZH2 polypeptide is represented by NCBI reference sequence NP_004447.

[0229] As used herein, "FLJ45974" refers to the gene encoding the FLJ45974 ncRNA. The FLJ45974 gene encodes the long intergenic non-protein-coding RNA 1446. FLJ45974 is also known as LINC01446. In some embodiments, the FLJ45974 gene is a human FLJ45974 gene. An exemplary FLJ45974 gene is represented by NCBI gene ID number 401337. An exemplary FLJ45974 ncRNA sequence is represented by NCBI reference sequence NR_038371.

[0230] As used herein, "ZNF479" refers to a gene encoding ZNF479 mRNA or polypeptide. The ZNF479 gene encodes the zinc finger protein 479 protein. ZNF479 is also known as KR19 and HKr19. In some embodiments, the ZNF479 gene is a human ZNF479 gene. An exemplary ZNF479 gene is represented by NCBI Gene ID number 90827. An exemplary ZNF479 mRNA sequence is represented by NCBI Reference Sequence NM_033273. An exemplary amino acid sequence of a ZNF479 polypeptide is represented by NCBI Reference Sequence NP_150376.

[0231] In some aspects, provided herein are ERBB2 fusion nucleic acid molecules comprising at least a portion of ERBB2 and at least a portion of another gene.

[0232] In some embodiments, an ERBB2 fusion nucleic acid molecule comprises at least a portion of ERBB2 and at least a portion of FBXL20, GRB7, MSI2, RANBP10, SEC14L1, WIPF2, PRKCA, or PPP1R1B. For example, in some embodiments, the ERBB2 fusion nucleic acid molecule is selected from FBXL20-ERBB2, GRB7-ERBB2, MSI2-ERBB2, RANBP10-ERBB2, SEC14L1-ERBB2, WIPF2-ERBB2, ERBB2-GRB7, ERBB2-PRKCA, or ERBB2-PPP1R1B, where the gene order is from 5' to 3'. Exemplary, non-limiting ERBB2 fusion nucleic acid molecules are described herein, and / or in Tables 1-6, and / or in the Examples herein.

[0233] As used herein, "FBXL20" refers to a gene encoding FBXL20 mRNA or polypeptide. The FBXL20 gene encodes the F-box and leucine-rich repeat protein 20 protein. FBXL20 is also known as Fbl2 and Fbl20. In some embodiments, the FBXL20 gene is a human FBXL20 gene. An exemplary FBXL20 gene is represented by NCBI Gene ID number 84961. An exemplary FBXL20 mRNA sequence is represented by NCBI Reference Sequence NM_032875. An exemplary amino acid sequence of the FBXL20 polypeptide is represented by NCBI Reference Sequence NP_116264.

[0234] As used herein, "MSI2" refers to a gene encoding MSI2 mRNA or polypeptide. The MSI2 gene encodes the musashi RNA-binding protein 2 protein. MSI2 is also known as MSI2H. In some embodiments, the MSI2 gene is a human MSI2 gene. An exemplary MSI2 gene is represented by NCBI gene ID number 124540. An exemplary MSI2 mRNA sequence is represented by NCBI reference sequence NM_138962. An exemplary amino acid sequence of the MSI2 polypeptide is represented by NCBI reference sequence NP_620412.

[0235] As used herein, "RANBP10" refers to a gene encoding RANBP10 mRNA or polypeptide. The RANBP10 gene encodes the RAN binding protein 10 protein. RANBP10 is also known as KIAA1464. In some embodiments, the RANBP10 gene is a human RANBP10 gene. An exemplary RANBP10 gene is represented by NCBI gene ID number 57610. An exemplary RANBP10 mRNA sequence is represented by NCBI reference sequence NM_020850. An exemplary amino acid sequence of a RANBP10 polypeptide is represented by NCBI reference sequence NP_065901.

[0236] As used herein, "SEC14L1" refers to a gene encoding a SEC14L1 mRNA or polypeptide. The SEC14L1 gene encodes the SEC14-like lipid-binding 1 protein. SEC14L1 is also known as SEC14L and PRELID4A. In some embodiments, the SEC14L1 gene is a human SEC14L1 gene. An exemplary SEC14L1 gene is represented by NCBI Gene ID number 6397. An exemplary SEC14L1 mRNA sequence is represented by NCBI Reference Sequence NM_003003. An exemplary amino acid sequence of a SEC14L1 polypeptide is represented by NCBI Reference Sequence NP_002994.

[0237] As used herein, "WIPF2" refers to a gene encoding WIPF2 mRNA or polypeptide. The WIPF2 gene encodes the WAS / WASL-interacting protein family member 2 protein. WIPF2 is also known as WICH and WIRE. In some embodiments, the WIPF2 gene is a human WIPF2 gene. An exemplary WIPF2 gene is represented by NCBI gene ID number 147179. An exemplary WIPF2 mRNA sequence is represented by NCBI reference sequence NM_133264. An exemplary amino acid sequence of a WIPF2 polypeptide is represented by NCBI reference sequence NP_57357.

[0238] As used herein, "GRB7" refers to a gene encoding GRB7 mRNA or polypeptide. The GRB7 gene encodes the growth factor receptor-bound protein 7 protein. In some embodiments, the GRB7 gene is a human GRB7 gene. An exemplary GRB7 gene is represented by NCBI Gene ID number 2886. An exemplary GRB7 mRNA sequence is represented by NCBI Reference Sequence NM_005310. An exemplary amino acid sequence of a GRB7 polypeptide is represented by NCBI Reference Sequence NP_005301.

[0239] As used herein, "PRKCA" refers to a gene encoding a PRKCA mRNA or polypeptide. The PRKCA gene encodes the protein kinase C alpha protein. PRKCA is also known as AAG6, PKCA, PRKACA, PKCI+ / -, PKCα, and PKC-α. In some embodiments, the PRKCA gene is a human PRKCA gene. An exemplary PRKCA gene is represented by NCBI gene ID number 5578. An exemplary PRKCA mRNA sequence is represented by NCBI reference sequence NM_002737. An exemplary amino acid sequence of a PRKCA polypeptide is represented by NCBI reference sequence NP_002728.

[0240] As used herein, "PPP1R1B" refers to a gene encoding a PPP1R1B mRNA or polypeptide. The PPP1R1B gene encodes the protein phosphatase 1 regulatory inhibitor subunit 1B protein. PPP1R1B is also known as DARPP32, DARPP-32, and FLJ20940. In some embodiments, the PPP1R1B gene is a human PPP1R1B gene. An exemplary PPP1R1B gene is represented by NCBI Gene ID number 84152. An exemplary PPP1R1B mRNA sequence is represented by NCBI Reference Sequence NM_032192. An exemplary amino acid sequence of a PPP1R1B polypeptide is represented by NCBI Reference Sequence NP_115568.

[0241] In some aspects, provided herein are FGFR1 fusion nucleic acid molecules comprising at least a portion of FGFR1 and at least a portion of another gene.

[0242] In some embodiments, an FGFR1 fusion nucleic acid molecule comprises at least a portion of FGFR1 and at least a portion of ADAM32, SLC12A8, ADAM18, BAG4, or TACC1. For example, in some embodiments, the FGFR1 fusion nucleic acid molecule is selected from FGFR1-ADAM32, FGFR1-SLC12A8, ADAM18-FGFR1, BAG4-FGFR1, or FGFR1-TACC1, where the gene order is from 5' to 3'. Exemplary, non-limiting FGFR1 fusion nucleic acid molecules are described herein, and / or in Tables 1-6, and / or in the Examples herein.

[0243] As used herein, "ADAM32" refers to a gene encoding an ADAM32 mRNA or polypeptide. The ADAM32 gene encodes an ADAM metallopeptidase domain 32 protein. In some embodiments, the ADAM32 gene is a human ADAM32 gene. An exemplary ADAM32 gene is represented by NCBI gene ID number 203102. An exemplary ADAM32 mRNA sequence is represented by NCBI reference sequence NM_145004. An exemplary amino acid sequence of an ADAM32 polypeptide is represented by NCBI reference sequence NP_659441.

[0244] As used herein, "SLC12A8" refers to a gene encoding SLC12A8 mRNA or polypeptide. The SLC12A8 gene encodes a solute carrier family 12 member 8 protein. SLC12A8 is also known as CCC9. In some embodiments, the SLC12A8 gene is human SLC12A8. An exemplary SLC12A8 gene is represented by NCBI gene ID number 84561. An exemplary SLC12A8 mRNA sequence is represented by NCBI reference sequence NM_024628. An exemplary amino acid sequence of a SLC12A8 polypeptide is represented by NCBI reference sequence NP_78904.

[0245] As used herein, "ADAM18" refers to a gene encoding an ADAM18 mRNA or polypeptide. The ADAM18 gene encodes an ADAM metallopeptidase domain 18 protein. ADAM18 is also known as ADAM27 and tMDCIII. In some embodiments, the ADAM18 gene is human ADAM18. An exemplary ADAM18 gene is represented by NCBI gene ID number 8749. An exemplary ADAM18 mRNA sequence is represented by NCBI reference sequence NM_14237. An exemplary amino acid sequence of an ADAM18 polypeptide is represented by NCBI reference sequence NP_055052.

[0246] As used herein, "BAG4" refers to a gene encoding a BAG4 mRNA or polypeptide. The BAG4 gene encodes the BAG co-chaperone 4 protein. BAG4 is also known as SODD and BAG-4. In some embodiments, the BAG4 gene is human BAG4. An exemplary BAG4 gene is represented by NCBI gene ID number 9530. An exemplary BAG4 mRNA sequence is represented by NCBI reference sequence NM_004874. An exemplary amino acid sequence of a BAG4 polypeptide is represented by NCBI reference sequence NP_004865.

[0247] As used herein, "TACC1" refers to a gene encoding TACC1 mRNA or polypeptide. The TACC1 gene encodes transforming acidic coiled-coil-containing protein 1 protein. TACC1 is also known as Ga55. In some embodiments, the TACC1 gene is human TACC1. An exemplary TACC1 gene is represented by NCBI Gene ID number 6867. An exemplary TACC1 mRNA sequence is represented by NCBI Reference Sequence NM_006283. An exemplary amino acid sequence of a TACC1 polypeptide is represented by NCBI Reference Sequence NP_006274.

[0248] In some aspects, provided herein are FGFR2 fusion nucleic acid molecules comprising at least a portion of FGFR2 and at least a portion of another gene.

[0249] In some embodiments, an FGFR2 fusion nucleic acid molecule comprises at least a portion of FGFR2 and at least a portion of AARSD1, ARMS2, ATF7, BAIAP2L1, CCAR1, CCSER2, CGNL1, EBF1, FANK1, FOXP1, CAMK2G, FLJ40288, GUCY2D, IQGAP2, PAWR, FLNB, IKZF2, KHDRBS1, MYOZ1, PCDH15, PRKAR1A, PRRC2A, RABGAP1, SCIN, STAU1, STK4, TIFA, TLK1, TRIM54, APIP, ATE1, BICC1, TFEC, GRB2, KIAA1217, KIAA1598, MACF1, MYH9, NRAP, RBM20, SPICE1, TACC2, VTI1A, WAC, WARS, or ZMYM4. For example, in some embodiments, the FGFR2 fusion nucleic acid molecule is selected from the group consisting of FGFR2-AARSD1, FGFR2-ARMS2, FGFR2-ATF7, FGFR2-BAIAP2L1, FGFR2-CCAR1, FGFR2-CCSER2, FGFR2-CGNL1, FGFR2-EBF1, FGFR2-FANK1, CAMK2G-FGFR2, FLJ40288-FGFR2, GUCY2D-FGFR2, IQGAP2-FGFR2, PAWR-FGFR2, FGFR2-FLNB, FGFR2-FOXP1, FGFR2-IKZF2, FGFR2-KHDRBS1, FGFR2-MYOZ1, FGFR2-PCDH15, FGFR2-PRKAR1A, FGFR2-PRRC2A, FGFR The gene is selected from 2-RABGAP1, FGFR2-SCIN, FGFR2-STAU1, FGFR2-STK4, FGFR2-TIFA, FGFR2-TLK1, FGFR2-TRIM54, FGFR2-APIP, FGFR2-ATE1, FGFR2-BICC1, TFEC-FGFR2, FGFR2-GRB2, FGFR2-KIAA1217, FGFR2-KIAA1598, FGFR2-MACF1, FGFR2-MYH9, FGFR2-NRAP, FGFR2-RBM20, FGFR2-SPICE1, FGFR2-TACC2, FGFR2-VTI1A, FGFR2-WAC, FGFR2-WARS, or FGFR2-ZMYM4, and the order of the genes is from 5' to 3'.Exemplary, non-limiting FGFR2 fusion nucleic acid molecules are described herein, and / or in Tables 1-6, and / or in the Examples herein.

[0250] As used herein, "AARSD1" refers to a gene encoding AARSD1 mRNA or polypeptide. The AARSD1 gene encodes the alanyl-tRNA synthetase domain-containing 1 protein. AARSD1 is also known as MGC2744 and AlaXp. In some embodiments, the AARSD1 gene is human AARSD1. An exemplary AARSD1 gene is represented by NCBI gene ID number 80755. An exemplary AARSD1 mRNA sequence is represented by NCBI reference sequence NM_001261434. An exemplary amino acid sequence of an AARSD1 polypeptide is represented by NCBI reference sequence NP_001248363.

[0251] As used herein, "ARMS2" refers to a gene encoding ARMS2 mRNA or polypeptide. The ARMS2 gene encodes age-related maculopathy susceptibility 2 protein. ARMS2 is also known as ARMD8 and LOC387715. In some embodiments, the ARMS2 gene is human ARMS2. An exemplary ARMS2 gene is represented by NCBI gene ID number 387715. An exemplary ARMS2 mRNA sequence is represented by NCBI reference sequence NM_001099667. An exemplary amino acid sequence of an ARMS2 polypeptide is represented by NCBI reference sequence NP_001093137.

[0252] As used herein, "ATF7" refers to a gene encoding an ATF7 mRNA or polypeptide. The ATF7 gene encodes the activating transcription factor 7 protein. ATF7 is also known as ATFA. In some embodiments, the ATF7 gene is human ATF7. An exemplary ATF7 gene is represented by NCBI gene ID number 11016. An exemplary ATF7 mRNA sequence is represented by NCBI reference sequence NM_006856. An exemplary amino acid sequence of an ATF7 polypeptide is represented by NCBI reference sequence NP_006847.

[0253] As used herein, "BAIAP2L1" refers to a gene encoding a BAIAP2L1 mRNA or polypeptide. The BAIAP2L1 gene encodes a BAR / IMD domain-containing adaptor protein 2-like 1 protein. BAIAP2L1 is also known as IRTKS. In some embodiments, the BAIAP2L1 gene is human BAIAP2L1. An exemplary BAIAP2L1 gene is represented by NCBI Gene ID number 55971. An exemplary BAIAP2L1 mRNA sequence is represented by NCBI Reference Sequence NM_018842. An exemplary amino acid sequence of a BAIAP2L1 polypeptide is represented by NCBI Reference Sequence NP_061330.

[0254] As used herein, "CCAR1" refers to a gene encoding a CCAR1 mRNA or polypeptide. The CCAR1 gene encodes the cell division cycle and apoptosis regulatory 1 protein. CCAR1 is also known as FLJ10590, CARP-1, and CARP1. In some embodiments, the CCAR1 gene is human CCAR1. An exemplary CCAR1 gene is represented by NCBI gene ID number 55749. An exemplary CCAR1 mRNA sequence is represented by NCBI reference sequence NM_018237. An exemplary amino acid sequence of a CCAR1 polypeptide is represented by NCBI reference sequence NP_060707.

[0255] As used herein, "CCSER2" refers to a gene encoding a CCSER2 mRNA or polypeptide. The CCSER2 gene encodes the coiled-coil serine-rich protein 2 protein. CCSER2 is also known as Gcap14, FAM190B, KIAA1128, and bA486O22.1. In some embodiments, the CCSER2 gene is human CCSER2. An exemplary CCSER2 gene is represented by NCBI gene ID number 54462. An exemplary CCSER2 mRNA sequence is represented by NCBI reference sequence NM_018999. An exemplary amino acid sequence of a CCSER2 polypeptide is represented by NCBI reference sequence NP_061872.

[0256] As used herein, "CGNL1" refers to a gene encoding a CGNL1 mRNA or polypeptide. The CGNL1 gene encodes the cingulin-like 1 protein. CGNL1 is also known as JACOP, FLJ14957, KIAA1749, and PCING. In some embodiments, the CGNL1 gene is human CGNL1. An exemplary CGNL1 gene is represented by NCBI gene ID number 84952. An exemplary CGNL1 mRNA sequence is represented by NCBI reference sequence NM_032866. An exemplary amino acid sequence of a CGNL1 polypeptide is represented by NCBI reference sequence NP_116255.

[0257] As used herein, "EBF1" refers to a gene encoding EBF1 mRNA or polypeptide. The EBF1 gene encodes the EBF transcription factor 1 protein. EBF1 is also known as EBF, COE1, OLF1, and O / E-1. In some embodiments, the EBF1 gene is human EBF1. An exemplary EBF1 gene is represented by NCBI Gene ID number 1879. An exemplary EBF1 mRNA sequence is represented by NCBI Reference Sequence NM_024007. An exemplary amino acid sequence of an EBF1 polypeptide is represented by NCBI Reference Sequence NP_076870.

[0258] As used herein, "FANK1" refers to a gene encoding FANK1 mRNA or polypeptide. The FANK1 gene encodes fibronectin type III and ankyrin repeat domain 1 protein. FANK1 is also known as HSD13. In some embodiments, the FANK1 gene is human FANK1. An exemplary FANK1 gene is represented by NCBI gene ID number 92565. An exemplary FANK1 mRNA sequence is represented by NCBI reference sequence NM_145235. An exemplary amino acid sequence of a FANK1 polypeptide is represented by NCBI reference sequence NP_660278.

[0259] As used herein, "FOXP1" refers to a gene encoding FOXP1 mRNA or polypeptide. The FOXP1 gene encodes the forkhead box P1 protein. FOXP1 is also known as MFH, QRF1, 12CC4, hFKH1B, and HSPC215. In some embodiments, the FOXP1 gene is human FOXP1. An exemplary FOXP1 gene is represented by NCBI gene ID number 27086. An exemplary FOXP1 mRNA sequence is represented by NCBI reference sequence NM_032682. An exemplary amino acid sequence of a FOXP1 polypeptide is represented by NCBI reference sequence NP_116071.

[0260] As used herein, "CAMK2G" refers to a gene encoding a CAMK2G mRNA or polypeptide. The CAMK2G gene encodes a calcium / calmodulin-dependent protein kinase II gamma protein. CAMK2G is also known as CAMK, CAMKG, MRD59, and CAMK-II. In some embodiments, the CAMK2G gene is human CAMK2G. An exemplary CAMK2G gene is represented by NCBI Gene ID number 818. An exemplary CAMK2G mRNA sequence is represented by NCBI Reference Sequence NM_001222. An exemplary amino acid sequence of a CAMK2G polypeptide is represented by NCBI Reference Sequence NP_001213.

[0261] As used herein, "FLJ40288" refers to the gene encoding FLJ40288 ncRNA. In some embodiments, the FLJ40288 gene is a human FLJ40288 gene. An exemplary FLJ40288 gene is represented by NCBI gene ID number 286023. An exemplary FLJ40288 ncRNA sequence is represented by NCBI reference sequence NR_046323.

[0262] As used herein, "GUCY2D" refers to a gene encoding a GUCY2D mRNA or polypeptide. The GUCY2D gene encodes a guanylate cyclase 2D protein. GUCY2D is also known as LCA, CG-E, CYGD, LCA1, RCD2, CACD1, CORD5, CORD6, GUC2D, ROSGC, retGC, CSNB1I, GUC1A4, RETGC-1, and ROS-GC1. In some embodiments, the GUCY2D gene is human GUCY2D. An exemplary GUCY2D gene is represented by NCBI Gene ID number 3000. An exemplary GUCY2D mRNA sequence is represented by NCBI Reference Sequence NM_000180. An exemplary amino acid sequence of a GUCY2D polypeptide is represented by NCBI Reference Sequence NP_000171.

[0263] As used herein, "IQGAP2" refers to a gene encoding IQGAP2 mRNA or polypeptide. The IQGAP2 gene encodes the IQ motif-containing GTPase-activating protein 2 protein. IQGAP2 is also known as LCA, CG-E, CYGD, LCA1, RCD2, CACD1, CORD5, CORD6, GUC2D, ROSGC, retGC, CSNB1I, GUC1A4, RETGC-1, and ROS-GC1. In some embodiments, the IQGAP2 gene is human IQGAP2. An exemplary IQGAP2 gene is represented by NCBI Gene ID number 10788. An exemplary IQGAP2 mRNA sequence is represented by NCBI Reference Sequence NM_006633. An exemplary amino acid sequence of an IQGAP2 polypeptide is represented by NCBI Reference Sequence NP_006624.

[0264] As used herein, "PAWR" refers to a gene encoding PAWR mRNA or polypeptide. The PAWR gene encodes a pro-apoptotic WT1-regulated protein. PAWR is also known as PAR4 and Par-4. In some embodiments, the PAWR gene is human PAWR. An exemplary PAWR gene is represented by NCBI gene ID number 5074. An exemplary PAWR mRNA sequence is represented by NCBI reference sequence NM_002583. An exemplary amino acid sequence of a PAWR polypeptide is represented by NCBI reference sequence NP_002574.

[0265] As used herein, "FLNB" refers to a gene encoding FLNB mRNA or polypeptide. The FLNB gene encodes the filamin B protein. FLNB is also known as AOI, FH1, SCT, TAP, LRS1, TABP, FLN-B, FLN1L, ABP-278, and ABP-280. In some embodiments, the FLNB gene is human FLNB. An exemplary FLNB gene is represented by NCBI Gene ID number 2317. An exemplary FLNB mRNA sequence is represented by NCBI Reference Sequence NM_001457. An exemplary amino acid sequence of a FLNB polypeptide is represented by NCBI Reference Sequence NP_001448.

[0266] As used herein, "IKZF2" refers to a gene encoding an IKZF2 mRNA or polypeptide. The IKZF2 gene encodes an IKAROS family zinc finger 2 protein. IKZF2 is also known as ANF1A2, HELIOS, ZNF1A2, and ZNFN1A2. In some embodiments, the IKZF2 gene is human IKZF2. An exemplary IKZF2 gene is represented by NCBI gene ID number 22807. An exemplary IKZF2 mRNA sequence is represented by NCBI reference sequence NM_001079526. An exemplary amino acid sequence of an IKZF2 polypeptide is represented by NCBI reference sequence NP_001072994.

[0267] As used herein, "KHDRBS1" refers to a gene encoding KHDRBS1 mRNA or polypeptide. The KHDRBS1 gene encodes the KH RNA-binding domain-containing signal transduction-related 1 protein. KHDRBS1 is also known as p62, p68, and Sam68. In some embodiments, the KHDRBS1 gene is human KHDRBS1. An exemplary KHDRBS1 gene is represented by NCBI gene ID number 10657. An exemplary KHDRBS1 mRNA sequence is represented by NCBI reference sequence NM_006559. An exemplary amino acid sequence of the KHDRBS1 polypeptide is represented by NCBI reference sequence NP_006550.

[0268] As used herein, "MYOZ1" refers to a gene encoding MYOZ1 mRNA or polypeptide. The MYOZ1 gene encodes the myozenin 1 protein. MYOZ1 is also known as p62, p68, and Sam68. In some embodiments, the MYOZ1 gene is human MYOZ1. An exemplary MYOZ1 gene is represented by NCBI gene ID number 58529. An exemplary MYOZ1 mRNA sequence is represented by NCBI reference sequence NM_021245. An exemplary amino acid sequence of a MYOZ1 polypeptide is represented by NCBI reference sequence NP_067068.

[0269] As used herein, "PCDH15" refers to a gene encoding PCDH15 mRNA or polypeptide. The PCDH15 gene encodes the protocadherin-related 15 protein. PCDH15 is also known as USH1F, CDHR15, and DFNB23. In some embodiments, the PCDH15 gene is human PCDH15. An exemplary PCDH15 gene is represented by NCBI gene ID number 65217. An exemplary PCDH15 mRNA sequence is represented by NCBI reference sequence NM_033056. An exemplary amino acid sequence of a PCDH15 polypeptide is represented by NCBI reference sequence NP_149045.

[0270] As used herein, "PRKAR1A" refers to a gene encoding a PRKAR1A mRNA or polypeptide. The PRKAR1A gene encodes a protein kinase cAMP-dependent type I regulatory subunit alpha protein. PRKAR1A is also known as CAR, CNC, CNC1, PKR1, TSE1, ADOHR, PPNAD1, PRKAR1, and ACRDYS1. In some embodiments, the PRKAR1A gene is human PRKAR1A. An exemplary PRKAR1A gene is represented by NCBI gene ID number 5573. An exemplary PRKAR1A mRNA sequence is represented by NCBI reference sequence NM_001278433. An exemplary amino acid sequence of a PRKAR1A polypeptide is represented by NCBI reference sequence NP_001265362.

[0271] As used herein, "PRRC2A" refers to a gene encoding a PRRC2A mRNA or polypeptide. The PRRC2A gene encodes a proline-rich coiled-coil 2A protein. PRRC2A is also known as CAR, CNC, CNC1, PKR1, TSE1, ADOHR, PPNAD1, PRKAR1, and ACRDYS1. In some embodiments, the PRRC2A gene is human PRRC2A. An exemplary PRRC2A gene is represented by NCBI Gene ID number 7916. An exemplary PRRC2A mRNA sequence is represented by NCBI Reference Sequence NM_004638. An exemplary amino acid sequence of a PRRC2A polypeptide is represented by NCBI Reference Sequence NP_004629.

[0272] As used herein, "RABGAP1" refers to a gene encoding RABGAP1 mRNA or polypeptide. The RABGAP1 gene encodes the RAB GTPase-activating protein 1 protein. RABGAP1 is also known as GAPCENA and TBC1D11. In some embodiments, the RABGAP1 gene is human RABGAP1. An exemplary RABGAP1 gene is represented by NCBI gene ID number 23637. An exemplary RABGAP1 mRNA sequence is represented by NCBI reference sequence NM_012197. An exemplary amino acid sequence of a RABGAP1 polypeptide is represented by NCBI reference sequence NP_036329.

[0273] As used herein, "SCIN" refers to a gene encoding a SCIN mRNA or polypeptide. The SCIN gene encodes the scinderin protein. SCIN is also known as KIAA1905. In some embodiments, the SCIN gene is human SCIN. An exemplary SCIN gene is represented by NCBI gene ID number 85477. An exemplary SCIN mRNA sequence is represented by NCBI reference sequence NM_033128. An exemplary amino acid sequence of a SCIN polypeptide is represented by NCBI reference sequence NP_149119.

[0274] As used herein, "STAU1" refers to a gene encoding STAU1 mRNA or polypeptide. The STAU1 gene encodes the Staufen double-stranded RNA-binding protein 1 protein. STAU1 is also known as STAU and PPP1R150. In some embodiments, the STAU1 gene is human STAU1. An exemplary STAU1 gene is represented by NCBI gene ID number 6780. An exemplary STAU1 mRNA sequence is represented by NCBI reference sequence NM_004602. An exemplary amino acid sequence of a STAU1 polypeptide is represented by NCBI reference sequence NP_004593.

[0275] As used herein, "STK4" refers to a gene encoding an STK4 mRNA or polypeptide. The STK4 gene encodes the serine / threonine kinase 4 protein. STK4 is also known as KRS2, MST1, and YSK3. In some embodiments, the STK4 gene is human STK4. An exemplary STK4 gene is represented by NCBI gene ID number 6789. An exemplary STK4 mRNA sequence is represented by NCBI reference sequence NM_006282. An exemplary amino acid sequence of an STK4 polypeptide is represented by NCBI reference sequence NP_006273.

[0276] As used herein, "TIFA" refers to a gene encoding a TIFA mRNA or polypeptide. The TIFA gene encodes a TRAF-interacting protein with a forkhead-associated domain. TIFA is also known as T2BP, T6BP, and TIFAA. In some embodiments, the TIFA gene is human TIFA. An exemplary TIFA gene is represented by NCBI gene ID number 92610. An exemplary TIFA mRNA sequence is represented by NCBI reference sequence NM_052864. An exemplary amino acid sequence of a TIFA polypeptide is represented by NCBI reference sequence NP_443096.

[0277] As used herein, "TLK1" refers to a gene encoding TLK1 mRNA or polypeptide. The TLK1 gene encodes the tousled-like kinase 1 protein. TLK1 is also known as PKU-beta. In some embodiments, the TLK1 gene is human TLK1. An exemplary TLK1 gene is represented by NCBI Gene ID number 9874. An exemplary TLK1 mRNA sequence is represented by NCBI Reference Sequence NM_012290. An exemplary amino acid sequence of a TLK1 polypeptide is represented by NCBI Reference Sequence NP_036422.

[0278] As used herein, "TRIM54" refers to a gene encoding a TRIM54 mRNA or polypeptide. The TRIM54 gene encodes a tripartite motif-containing 54 protein. TRIM54 is also known as MURF, MURF-3, RNF30, and muRF3. In some embodiments, the TRIM54 gene is human TRIM54. An exemplary TRIM54 gene is represented by NCBI gene ID number 57159. An exemplary TRIM54 mRNA sequence is represented by NCBI reference sequence NM_032546. An exemplary amino acid sequence of a TRIM54 polypeptide is represented by NCBI reference sequence NP_115935.

[0279] As used herein, "APIP" refers to a gene encoding an APIP mRNA or polypeptide. The APIP gene encodes an APAF1-interacting protein. APIP is also known as APIP2, CGI-29, CGI29, MMRP19, and hAPIP. In some embodiments, the APIP gene is human APIP. An exemplary APIP gene is represented by NCBI gene ID number 51074. An exemplary APIP mRNA sequence is represented by NCBI reference sequence NM_015957. An exemplary amino acid sequence of an APIP polypeptide is represented by NCBI reference sequence NP_057041.

[0280] As used herein, "ATE1" refers to a gene encoding an ATE1 mRNA or polypeptide. The ATE1 gene encodes the arginine transferase 1 protein. ATE1 is also known as APIP2, CGI-29, CGI29, MMRP19, and hAPIP. In some embodiments, the ATE1 gene is human ATE1. An exemplary ATE1 gene is represented by NCBI gene ID number 11101. An exemplary ATE1 mRNA sequence is represented by NCBI reference sequence NM_007041. An exemplary amino acid sequence of an ATE1 polypeptide is represented by NCBI reference sequence NP_008972.

[0281] As used herein, "BICC1" refers to a gene encoding a BICC1 mRNA or polypeptide. The BICC1 gene encodes the BicC family RNA-binding protein 1 protein. BICC1 is also known as BICC and CYSRD. In some embodiments, the BICC1 gene is human BICC1. An exemplary BICC1 gene is represented by NCBI Gene ID number 80114. An exemplary BICC1 mRNA sequence is represented by NCBI Reference Sequence NM_001080512. An exemplary amino acid sequence of a BICC1 polypeptide is represented by NCBI Reference Sequence NP_001073981.

[0282] As used herein, "TFEC" refers to a gene encoding a TFEC mRNA or polypeptide. The TFEC gene encodes a transcription factor EC protein. TFEC is also known as TCFEC, TFE-C, TFEC-L, TFECL, bHLHe34, and hTFEC-L. In some embodiments, the TFEC gene is human TFEC. An exemplary TFEC gene is represented by NCBI gene ID number 22797. An exemplary TFEC mRNA sequence is represented by NCBI reference sequence NM_012252. An exemplary amino acid sequence of a TFEC polypeptide is represented by NCBI reference sequence NP_036384.

[0283] As used herein, "GRB2" refers to a gene encoding GRB2 mRNA or polypeptide. The GRB2 gene encodes the growth factor receptor-bound protein 2 protein. GRB2 is also known as ASH, EGFRBP-GRB2, Grb3-3, MST084, MSTP084, and NCKAP2. In some embodiments, the GRB2 gene is human GRB2. An exemplary GRB2 gene is represented by NCBI Gene ID number 2885. An exemplary GRB2 mRNA sequence is represented by NCBI Reference Sequence NM_002086. An exemplary amino acid sequence of a GRB2 polypeptide is represented by NCBI Reference Sequence NP_002077.

[0284] As used herein, "KIAA1217" refers to a gene encoding KIAA1217 mRNA or polypeptide. The KIAA1217 gene encodes the KIAA1217 protein. KIAA1217 is also known as ETL4 and SKT. In some embodiments, the KIAA1217 gene is human KIAA1217. An exemplary KIAA1217 gene is represented by NCBI gene ID number 56243. An exemplary KIAA1217 mRNA sequence is represented by NCBI reference sequence NM_019590. An exemplary amino acid sequence of the KIAA1217 polypeptide is represented by NCBI reference sequence NP_062536.

[0285] As used herein, "KIAA1598" refers to a gene encoding KIAA1598 mRNA or polypeptide. The KIAA1598 gene encodes the KIAA1598 protein. KIAA1598 is also known as shootin-1 and SHTN1. In some embodiments, the KIAA1598 gene is human KIAA1598. An exemplary KIAA1598 gene is represented by NCBI gene ID number 57698. An exemplary KIAA1598 mRNA sequence is represented by NCBI reference sequence NM_018330. An exemplary amino acid sequence of a KIAA1598 polypeptide is represented by NCBI reference sequence NP_060800.

[0286] As used herein, "MACF1" refers to a gene encoding MACF1 mRNA or polypeptide. The MACF1 gene encodes the microtubule-actin cross-linking factor 1 protein. MACF1 is also known as ABP620, ACF7, LIS9, Lnc-PMIF, MACF, and OFC4. In some embodiments, the MACF1 gene is human MACF1. An exemplary MACF1 gene is represented by NCBI gene ID number 23499. An exemplary MACF1 mRNA sequence is represented by NCBI reference sequence NM_012090. An exemplary amino acid sequence of a MACF1 polypeptide is represented by NCBI reference sequence NP_036222.

[0287] As used herein, "MYH9" refers to a gene encoding MYH9 mRNA or polypeptide. The MYH9 gene encodes the myosin heavy chain 9 protein. MYH9 is also known as BDPLT6, DFNA17, EPSTS, FTNS, MATINS, MHA, NMHC-II-A, NMMHC-IIA, and NMMHCA. In some embodiments, the MYH9 gene is human MYH9. An exemplary MYH9 gene is represented by NCBI Gene ID number 4627. An exemplary MYH9 mRNA sequence is represented by NCBI Reference Sequence NM_002473. An exemplary amino acid sequence of a MYH9 polypeptide is represented by NCBI Reference Sequence NP_002464.

[0288] As used herein, "NRAP" refers to a gene encoding NRAP mRNA or polypeptide. The NRAP gene encodes a nebulin-associated anchor protein. NRAP is also known as N-RAP. In some embodiments, the NRAP gene is human NRAP. An exemplary NRAP gene is represented by NCBI gene ID number 4892. An exemplary NRAP mRNA sequence is represented by NCBI reference sequence NM_006175. An exemplary amino acid sequence of an NRAP polypeptide is represented by NCBI reference sequence NP_006166.

[0289] As used herein, "RBM20" refers to a gene encoding RBM20 mRNA or polypeptide. The RBM20 gene encodes RNA-binding motif protein 20 protein. In some embodiments, the RBM20 gene is human RBM20. An exemplary RBM20 gene is represented by NCBI gene ID number 282996. An exemplary RBM20 mRNA sequence is represented by NCBI reference sequence NM_001134363. An exemplary amino acid sequence of the RBM20 polypeptide is represented by NCBI reference sequence NP_001127835.

[0290] As used herein, "SPICE1" refers to a gene encoding a SPICE1 mRNA or polypeptide. The SPICE1 gene encodes the spindle-and-centriole-associated protein 1 protein. SPICE1 is also known as CCDC52 and SPICE. In some embodiments, the SPICE1 gene is human SPICE1. An exemplary SPICE1 gene is represented by NCBI gene ID number 152185. An exemplary SPICE1 mRNA sequence is represented by NCBI reference sequence NM_144718. An exemplary amino acid sequence of a SPICE1 polypeptide is represented by NCBI reference sequence NP_653319.

[0291] As used herein, "TACC2" refers to a gene encoding a TACC2 mRNA or polypeptide. The TACC2 gene encodes the transforming acidic coiled-coil-containing protein 2 protein. TACC2 is also known as AZU-1 and ECTACC. In some embodiments, the TACC2 gene is human TACC2. An exemplary TACC2 gene is represented by NCBI Gene ID number 10579. An exemplary TACC2 mRNA sequence is represented by NCBI Reference Sequence NM_006997. An exemplary amino acid sequence of a TACC2 polypeptide is represented by NCBI Reference Sequence NP_008928.

[0292] As used herein, "VTI1A" refers to a gene encoding a VTI1A mRNA or polypeptide. The VTI1A gene encodes a vesicle transport 1A protein that interacts with t-SNAREs. VTI1A is also known as MMDS3, MVti1, VTI1RP2, and Vti1-rp2. In some embodiments, the VTI1A gene is human VTI1A. An exemplary VTI1A gene is represented by NCBI Gene ID number 143187. An exemplary VTI1A mRNA sequence is represented by NCBI Reference Sequence NM_145206. An exemplary amino acid sequence of a VTI1A polypeptide is represented by NCBI Reference Sequence NP_660207.

[0293] As used herein, "WAC" refers to a gene encoding a WAC mRNA or polypeptide. The WAC gene encodes a coiled-coil WW domain-containing adaptor protein. WAC is also known as BM-016, DESSH, PRO1741, and Wwp4. In some embodiments, the WAC gene is human WAC. An exemplary WAC gene is represented by NCBI gene ID number 51322. An exemplary WAC mRNA sequence is represented by NCBI reference sequence NM_016628. An exemplary amino acid sequence of a WAC polypeptide is represented by NCBI reference sequence NP_057712.

[0294] As used herein, "WARS" refers to a gene encoding a WARS mRNA or polypeptide. The WARS gene encodes a tryptophanyl-tRNA synthetase protein. WARS is also known as TrpRS, WRS, and Wars1. In some embodiments, the WARS gene is human WARS. An exemplary WARS gene is represented by NCBI gene ID number 7453. An exemplary WARS mRNA sequence is represented by NCBI reference sequence NM_004184. An exemplary amino acid sequence of a WARS polypeptide is represented by NCBI reference sequence NP_004175.

[0295] As used herein, "ZMYM4" refers to a gene encoding ZMYM4 mRNA or polypeptide. The ZMYM4 gene encodes the zinc finger MYM-type containing 4 protein. ZMYM4 is also known as CDIR, MYM, ZNF198L3, and ZNF262. In some embodiments, the ZMYM4 gene is human ZMYM4. An exemplary ZMYM4 gene is represented by NCBI gene ID number 9202. An exemplary ZMYM4 mRNA sequence is represented by NCBI reference sequence NM_005095. An exemplary amino acid sequence of a ZMYM4 polypeptide is represented by NCBI reference sequence NP_005086.

[0296] In some aspects, provided herein are FGFR3 fusion nucleic acid molecules comprising at least a portion of FGFR3 and at least a portion of another gene.

[0297] In some embodiments, an FGFR3 fusion nucleic acid molecule comprises at least a portion of FGFR3 and at least a portion of CCT5, CNOT4, TNIP2, IGH, TACC3, ADD1, or WHSC1. For example, in some embodiments, the FGFR3 fusion nucleic acid molecule is selected from FGFR3-CCT5, FGFR3-CNOT4, FGFR3-TNIP2, FGFR3-ADD1, FGFR3-IGH, FGFR3-TACC3, or FGFR3-WHSC1, with the gene order being 5' to 3'. Exemplary, non-limiting FGFR3 fusion nucleic acid molecules are described herein, and / or in Tables 1-6, and / or in the Examples herein.

[0298] As used herein, "CCT5" refers to a gene encoding a CCT5 mRNA or polypeptide. The CCT5 gene encodes the chaperonin-containing TCP1 subunit 5 protein. CCT5 is also known as CCT-epsilon, CCTE, HEL-S-69, PNAS-102, and TCP-1-epsilon. In some embodiments, the CCT5 gene is human CCT5. An exemplary CCT5 gene is represented by NCBI gene ID number 22948. An exemplary CCT5 mRNA sequence is represented by NCBI reference sequence NM_012073. An exemplary amino acid sequence of a CCT5 polypeptide is represented by NCBI reference sequence NP_036205.

[0299] As used herein, "CNOT4" refers to a gene encoding a CNOT4 mRNA or polypeptide. The CNOT4 gene encodes the CCR4-NOT transcription complex subunit 4 protein. CNOT4 is also known as CLONE243, NOT4, and NOT4H. In some embodiments, the CNOT4 gene is human CNOT4. An exemplary CNOT4 gene is represented by NCBI gene ID number 4850. An exemplary CNOT4 mRNA sequence is represented by NCBI reference sequence NM_013316. An exemplary amino acid sequence of a CNOT4 polypeptide is represented by NCBI reference sequence NP_037448.

[0300] As used herein, "TNIP2" refers to a gene encoding TNIP2 mRNA or polypeptide. The TNIP2 gene encodes the TNFAIP3-interacting protein 2 protein. TNIP2 is also known as ABIN2, FLIP1, and KLIP. In some embodiments, the TNIP2 gene is human TNIP2. An exemplary TNIP2 gene is represented by NCBI gene ID number 79155. An exemplary TNIP2 mRNA sequence is represented by NCBI reference sequence NM_024309. An exemplary amino acid sequence of a TNIP2 polypeptide is represented by NCBI reference sequence NP_077285.

[0301] As used herein, "IGH" refers to a gene encoding an IGH mRNA or polypeptide. The IGH gene encodes an immunoglobulin heavy chain locus protein. IGH is also known as IGD1, IGH@, IGH@, IGHD@, IGHDY1, IGHJ, IGHJ@, IGHV, and IGHV@. In some embodiments, the IGH gene is human IGH. An exemplary IGH gene is represented by NCBI gene ID number 3492. An exemplary IGH DNA sequence is represented by NCBI reference sequence NG_001019.

[0302] As used herein, "TACC3" refers to a gene encoding a TACC3 mRNA or polypeptide. The TACC3 gene encodes the transforming acidic coiled-coil-containing protein 3 protein. TACC3 is also known as ERIC-1, ERIC1, Tacc4, and maskin. In some embodiments, the TACC3 gene is human TACC3. An exemplary TACC3 gene is represented by NCBI Gene ID number 10460. An exemplary TACC3 mRNA sequence is represented by NCBI Reference Sequence NM_006342. An exemplary amino acid sequence of a TACC3 polypeptide is represented by NCBI Reference Sequence NP_006333.

[0303] As used herein, "ADD1" refers to a gene encoding an ADD1 mRNA or polypeptide. The ADD1 gene encodes the Adduction 1 protein. ADD1 is also known as ADDA. In some embodiments, the ADD1 gene is human ADD1. An exemplary ADD1 gene is represented by NCBI Gene ID number 118. An exemplary ADD1 mRNA sequence is represented by NCBI Reference Sequence NM_001119. An exemplary amino acid sequence of an ADD1 polypeptide is represented by NCBI Reference Sequence NP_001110.

[0304] As used herein, "WHSC1" refers to a gene encoding WHSC1 mRNA or polypeptide. The WHSC1 gene encodes Wolf-Hirschorn syndrome candidate 1 protein. WHSC1 is also known as KMT3F, KMT3G, MMSET, REIIBP, TRX5, WHS, and NSD2. In some embodiments, the WHSC1 gene is human WHSC1. An exemplary WHSC1 gene is represented by NCBI gene ID number 7468. An exemplary WHSC1 mRNA sequence is represented by NCBI reference sequence NM_133330. An exemplary amino acid sequence of a WHSC1 polypeptide is represented by NCBI reference sequence NP_579877.

[0305] In some aspects, provided herein are MET fusion nucleic acid molecules comprising at least a portion of MET and at least a portion of another gene.

[0306] In some embodiments, a MET fusion nucleic acid molecule comprises at least a portion of MET and at least a portion of LDHA, CNTNAP2, HBP1, SNRNP70, CAPZA2, or ST7. For example, in some embodiments, the MET fusion nucleic acid molecule is selected from MET-LDHA, CNTNAP2-MET, HBP1-MET, SNRNP70-MET, MET-CAPZA2, or ST7-MET, where the gene order is from 5' to 3'. Exemplary, non-limiting MET fusion nucleic acid molecules are described herein, and / or in Tables 1-6, and / or in the Examples herein.

[0307] As used herein, "LDHA" refers to a gene encoding an LDHA mRNA or polypeptide. The LDHA gene encodes the lactate dehydrogenase A protein. LDHA is also known as GSD11, HEL-S-133P, LDHM, and PIG19. In some embodiments, the LDHA gene is human LDHA. An exemplary LDHA gene is represented by NCBI gene ID number 3939. An exemplary LDHA mRNA sequence is represented by NCBI reference sequence NM_005566. An exemplary amino acid sequence of an LDHA polypeptide is represented by NCBI reference sequence NP_005557.

[0308] As used herein, "CNTNAP2" refers to a gene encoding CNTNAP2 mRNA or polypeptide. The CNTNAP2 gene encodes the contactin-associated protein 2 protein. CNTNAP2 is also known as AUTS15, CASPR2, CDFE, NRXN4, and PTHSL1. In some embodiments, the CNTNAP2 gene is human CNTNAP2. An exemplary CNTNAP2 gene is represented by NCBI Gene ID number 26047. An exemplary CNTNAP2 mRNA sequence is represented by NCBI Reference Sequence NM_014141. An exemplary amino acid sequence of a CNTNAP2 polypeptide is represented by NCBI Reference Sequence NP_054860.

[0309] As used herein, "HBP1" refers to a gene encoding HBP1 mRNA or polypeptide. The HBP1 gene encodes the HMG box transcription factor 1 protein. In some embodiments, the HBP1 gene is human HBP1. An exemplary HBP1 gene is represented by NCBI Gene ID number 26959. An exemplary HBP1 mRNA sequence is represented by NCBI Reference Sequence NM_012257. An exemplary amino acid sequence of an HBP1 polypeptide is represented by NCBI Reference Sequence NP_036389.

[0310] As used herein, "SNRNP70" refers to a gene encoding SNRNP70 mRNA or polypeptide. The SNRNP70 gene encodes the small nuclear ribonucleoprotein U1 subunit 70 protein. SNRNP70 is also known as RNPU1Z, RPU1, SNRP70, Snp1, U1-70K, U170K, U1AP, and U1RNP. In some embodiments, the SNRNP70 gene is human SNRNP70. An exemplary SNRNP70 gene is represented by NCBI Gene ID number 6625. An exemplary SNRNP70 mRNA sequence is represented by NCBI Reference Sequence NM_003089. An exemplary amino acid sequence of a SNRNP70 polypeptide is represented by NCBI Reference Sequence NP_003080.

[0311] As used herein, "CAPZA2" refers to a gene encoding a CAPZA2 mRNA or polypeptide. The CAPZA2 gene encodes the capping actin protein subunit alpha 2 protein of the muscle Z line. CAPZA2 is also known as CAPPA2 and CAPZ. In some embodiments, the CAPZA2 gene is human CAPZA2. An exemplary CAPZA2 gene is represented by NCBI Gene ID number 830. An exemplary CAPZA2 mRNA sequence is represented by NCBI Reference Sequence NM_006136. An exemplary amino acid sequence of a CAPZA2 polypeptide is represented by NCBI Reference Sequence NP_006127.

[0312] As used herein, "ST7" refers to a gene encoding an ST7 mRNA or polypeptide. The ST7 gene encodes the suppressor of tumorigenicity 7 protein. ST7 is also known as ETS7q, FAM4A, FAM4A1, HELG, RAY1, SEN4, and TSG7. In some embodiments, the ST7 gene is human ST7. An exemplary ST7 gene is represented by NCBI gene ID number 7982. An exemplary ST7 mRNA sequence is represented by NCBI reference sequence NM_018412. An exemplary amino acid sequence of an ST7 polypeptide is represented by NCBI reference sequence NP_060882.

[0313] In some aspects, provided herein are NTRK1 fusion nucleic acid molecules comprising at least a portion of NTRK1 and at least a portion of another gene.

[0314] In some embodiments, the NTRK1 fusion nucleic acid molecule comprises at least a portion of NTRK1 and at least a portion of MEF2D. For example, in some embodiments, the NTRK1 fusion nucleic acid molecule is an NTRK1-MEF2D fusion nucleic acid molecule, and the gene order is from 5' to 3'. Exemplary, non-limiting NTRK1 fusion nucleic acid molecules are described herein, and / or in Tables 2 and 6, and / or in the Examples herein.

[0315] As used herein, "MEF2D" refers to a gene encoding MEF2D mRNA or polypeptide. The MEF2D gene encodes the myocyte enhancer factor 2D protein. In some embodiments, the MEF2D gene is human MEF2D. An exemplary MEF2D gene is represented by NCBI gene ID number 4209. An exemplary MEF2D mRNA sequence is represented by NCBI reference sequence NM_005920. An exemplary amino acid sequence of a MEF2D polypeptide is represented by NCBI reference sequence NP_005911.

[0316] In some aspects, provided herein are RAF1 fusion nucleic acid molecules comprising at least a portion of RAF1 and at least a portion of another gene.

[0317] In some embodiments, a RAF1 fusion nucleic acid molecule comprises at least a portion of RAF1 and at least a portion of a POC1A, SYN2, TRAK1, or ZFYVE20 gene. For example, in some embodiments, the RAF1 fusion nucleic acid molecule is selected from POC1A-RAF1, SYN2-RAF1, ZFYVE20-RAF1, or RAF1-TRAK1, where the order of the genes is from 5' to 3'. Exemplary, non-limiting RAF1 fusion nucleic acid molecules are described herein, and / or in Tables 1-6, and / or in the Examples herein.

[0318] As used herein, "POC1A" refers to a gene encoding a POC1A mRNA or polypeptide. The POC1A gene encodes the POC1 centriole A protein. POC1A is also known as PIX2, SOFT, and WDR51A. In some embodiments, the POC1A gene is human POC1A. An exemplary POC1A gene is represented by NCBI Gene ID number 25886. An exemplary POC1A mRNA sequence is represented by NCBI Reference Sequence NM_015426. An exemplary amino acid sequence of a POC1A polypeptide is represented by NCBI Reference Sequence NP_056241.

[0319] As used herein, "SYN2" refers to a gene encoding a SYN2 mRNA or polypeptide. The SYN2 gene encodes the synapsin II protein. SYN2 is also known as SYNII. In some embodiments, the SYN2 gene is human SYN2. An exemplary SYN2 gene is represented by NCBI gene ID number 6854. An exemplary SYN2 mRNA sequence is represented by NCBI reference sequence NM_003178. An exemplary amino acid sequence of a SYN2 polypeptide is represented by NCBI reference sequence NP_003169.

[0320] As used herein, "TRAK1" refers to a gene encoding a TRAK1 mRNA or polypeptide. The TRAK1 gene encodes the transport kinesin protein 1 protein. TRAK1 is also known as DEE68, EIEE68, MILT1, and OIP106. In some embodiments, the TRAK1 gene is human TRAK1. An exemplary TRAK1 gene is represented by NCBI gene ID number 22906. An exemplary TRAK1 mRNA sequence is represented by NCBI reference sequence NM_014965. An exemplary amino acid sequence of a TRAK1 polypeptide is represented by NCBI reference sequence NP_055780.

[0321] As used herein, "ZFYVE20" refers to a gene encoding ZFYVE20 mRNA or polypeptide. The ZFYVE20 gene encodes the ravenosyn-5 protein. ZFYVE20 is also known as ravenosyn-5 and RBSN. In some embodiments, the ZFYVE20 gene is human ZFYVE20. An exemplary ZFYVE20 gene is represented by NCBI gene ID number 64145. An exemplary ZFYVE20 mRNA sequence is represented by NCBI reference sequence NM_022340. An exemplary amino acid sequence of a ZFYVE20 polypeptide is represented by NCBI reference sequence NP_071735.

[0322] In some aspects, provided herein are RET fusion nucleic acid molecules comprising at least a portion of RET and at least a portion of another gene.

[0323] In some embodiments, the RET fusion nucleic acid molecule comprises at least a portion of RET and at least a portion of ADCY1, NPY4R, PAWR, ALOX5, ARID5B, DHX32, PDE5A, ZNF365, BAIAP2L1, CSGALNACT2, GPHN, NCOA4, RASGEFlA, KIAA1217, CCDC6, ERC1, KIF5B, TRIM24, or VCL. For example, in some embodiments, the RET fusion nucleic acid molecule is selected from RET-ADCY1, RET-NPY4R, RET-PAWR, ALOX5-RET, ARID5B-RET, DHX32-RET, PDE5A-RET, ZNF365-RET, BAIAP2L1-RET, RET-CSGALNACT2, RET-GPHN, NCOA4-RET, RET-RASGEF1A, KIAA1217-RET, CCDC6-RET, ERC1-RET, KIF5B-RET, TRIM24-RET, or VCL-RET, with the order of the genes being from 5' to 3'. Exemplary, non-limiting RET fusion nucleic acid molecules are described herein, and / or in Tables 1-6, and / or in the Examples herein.

[0324] As used herein, "ADCY1" refers to a gene encoding ADCY1 mRNA or polypeptide. The ADCY1 gene encodes the adenylate cyclase 1 protein. ADCY1 is also known as AC1 and DFNB44. In some embodiments, the ADCY1 gene is human ADCY1. An exemplary ADCY1 gene is represented by NCBI Gene ID number 107. An exemplary ADCY1 mRNA sequence is represented by NCBI Reference Sequence NM_021116. An exemplary amino acid sequence of an ADCY1 polypeptide is represented by NCBI Reference Sequence NP_066939.

[0325] As used herein, "NPY4R" refers to a gene encoding an NPY4R mRNA or polypeptide. The NPY4R gene encodes the neuropeptide Y receptor Y4 protein. NPY4R is also known as NPY4-R, PP1, PPYR1, and Y4. In some embodiments, the NPY4R gene is human NPY4R. An exemplary NPY4R gene is represented by NCBI Gene ID number 5540. An exemplary NPY4R mRNA sequence is represented by NCBI Reference Sequence NM_005972. An exemplary amino acid sequence of an NPY4R polypeptide is represented by NCBI Reference Sequence NP_005963.

[0326] As used herein, "PAWR" refers to a gene encoding PAWR mRNA or polypeptide. The PAWR gene encodes a pro-apoptotic WT1-regulated protein. PAWR is also known as PAR4 and Par-4. In some embodiments, the PAWR gene is human PAWR. An exemplary PAWR gene is represented by NCBI gene ID number 5074. An exemplary PAWR mRNA sequence is represented by NCBI reference sequence NM_002583. An exemplary amino acid sequence of a PAWR polypeptide is represented by NCBI reference sequence NP_002574.

[0327] As used herein, "ALOX5" refers to a gene encoding ALOX5 mRNA or polypeptide. The ALOX5 gene encodes the arachidonate 5-lipoxygenase protein. ALOX5 is also known as 5-LO, 5-LOX, 5LPG, and LOG5. In some embodiments, the ALOX5 gene is human ALOX5. An exemplary ALOX5 gene is represented by NCBI Gene ID number 240. An exemplary ALOX5 mRNA sequence is represented by NCBI Reference Sequence NM_000698. An exemplary amino acid sequence of an ALOX5 polypeptide is represented by NCBI Reference Sequence NP_000689.

[0328] As used herein, "ARID5B" refers to a gene encoding ARID5B mRNA or polypeptide. The ARID5B gene encodes the AT-rich interaction domain 5B protein. ARID5B is also known as 5 DESRT, MRF-2, and MRF2. In some embodiments, the ARID5B gene is human ARID5B. An exemplary ARID5B gene is represented by NCBI gene ID number 84159. An exemplary ARID5B mRNA sequence is represented by NCBI reference sequence NM_032199. An exemplary amino acid sequence of an ARID5B polypeptide is represented by NCBI reference sequence NP_115575.

[0329] As used herein, "DHX32" refers to a gene encoding a DHX32 mRNA or polypeptide. The DHX32 gene encodes the DEAH-box helicase 32 protein. DHX32 is also known as DDX32 and DHLP1. In some embodiments, the DHX32 gene is human DHX32. An exemplary DHX32 gene is represented by NCBI gene ID number 55760. An exemplary DHX32 mRNA sequence is represented by NCBI reference sequence NM_018180. An exemplary amino acid sequence of a DHX32 polypeptide is represented by NCBI reference sequence NP_060650.

[0330] As used herein, "PDE5A" refers to a gene encoding a PDE5A mRNA or polypeptide. The PDE5A gene encodes a phosphodiesterase 5A protein. PDE5A is also known as CGB-PDE, CN5A, and PDE5. In some embodiments, the PDE5A gene is human PDE5A. An exemplary PDE5A gene is represented by NCBI gene ID number 8654. An exemplary PDE5A mRNA sequence is represented by NCBI reference sequence NM_001083. An exemplary amino acid sequence of a PDE5A polypeptide is represented by NCBI reference sequence NP_001074.

[0331] As used herein, "ZNF365" refers to a gene encoding ZNF365 mRNA or polypeptide. The ZNF365 gene encodes the zinc finger protein 365 protein. ZNF365 is also known as Su48, UAN, and ZNF365D. In some embodiments, the ZNF365 gene is human ZNF365. An exemplary ZNF365 gene is represented by NCBI Gene ID number 22891. An exemplary ZNF365 mRNA sequence is represented by NCBI Reference Sequence NM_014951. An exemplary amino acid sequence of a ZNF365 polypeptide is represented by NCBI Reference Sequence NP_055766.

[0332] As used herein, "BAIAP2L1" refers to a gene encoding a BAIAP2L1 mRNA or polypeptide. The BAIAP2L1 gene encodes a BAR / IMD domain-containing adaptor protein 2-like 1 protein. BAIAP2L1 is also known as IRTKS. In some embodiments, the BAIAP2L1 gene is human BAIAP2L1. An exemplary BAIAP2L1 gene is represented by NCBI Gene ID number 55971. An exemplary BAIAP2L1 mRNA sequence is represented by NCBI Reference Sequence NM_018842. An exemplary amino acid sequence of a BAIAP2L1 polypeptide is represented by NCBI Reference Sequence NP_061330.

[0333] As used herein, "CSGALNACT2" refers to a gene encoding a CSGALNACT2 mRNA or polypeptide. The CSGALNACT2 gene encodes the chondroitin sulfate N-acetylgalactosaminyltransferase 2 protein. CSGALNACT2 is also known as CHGN2, ChGn-2, GALNACT-2, GALNACT2, PRO0082, and beta4GalNAcT. In some embodiments, the CSGALNACT2 gene is human CSGALNACT2. An exemplary CSGALNACT2 gene is represented by NCBI Gene ID number 55454. An exemplary CSGALNACT2 mRNA sequence is represented by NCBI Reference Sequence NM_018590. An exemplary amino acid sequence of a CSGALNACT2 polypeptide is represented by NCBI Reference Sequence NP_061060.

[0334] As used herein, "GPHN" refers to a gene encoding a GPHN mRNA or polypeptide. The GPHN gene encodes the gephyrin protein. GPHN is also known as GEPH, GPH, GPHRYN, HKPX1, and MOCODC. In some embodiments, the GPHN gene is human GPHN. An exemplary GPHN gene is represented by NCBI gene ID number 10243. An exemplary GPHN mRNA sequence is represented by NCBI reference sequence NM_020806. An exemplary amino acid sequence of a GPHN polypeptide is represented by NCBI reference sequence NP_065857.

[0335] As used herein, "NCOA4" refers to a gene encoding NCOA4 mRNA or polypeptide. The NCOA4 gene encodes the nuclear receptor coactivator 4 protein. NCOA4 is also known as ARA70, ELE1, PTC3, and RFG. In some embodiments, the NCOA4 gene is human NCOA4. An exemplary NCOA4 gene is represented by NCBI gene ID number 8031. An exemplary NCOA4 mRNA sequence is represented by NCBI reference sequence NM_005437. An exemplary amino acid sequence of an NCOA4 polypeptide is represented by NCBI reference sequence NP_005428.

[0336] As used herein, "RASGEF1A" refers to a gene encoding a RASGEF1A mRNA or polypeptide. The RASGEF1A gene encodes the RasGEF domain family member 1A protein. RASGEF1A is also known as CG4853. In some embodiments, the RASGEF1A gene is human RASGEF1A. An exemplary RASGEF1A gene is represented by NCBI gene ID number 221002. An exemplary RASGEF1A mRNA sequence is represented by NCBI reference sequence NM_145313. An exemplary amino acid sequence of a RASGEF1A polypeptide is represented by NCBI reference sequence NP_660356.

[0337] As used herein, "CCDC6" refers to a gene encoding a CCDC6 mRNA or polypeptide. The CCDC6 gene encodes a coiled-coil domain-containing 6 protein. CCDC6 is also known as D10S170, H4, PTC, TPC, and TST1. In some embodiments, the CCDC6 gene is human CCDC6. An exemplary CCDC6 gene is represented by NCBI gene ID number 8030. An exemplary CCDC6 mRNA sequence is represented by NCBI reference sequence NM_005436. An exemplary amino acid sequence of a CCDC6 polypeptide is represented by NCBI reference sequence NP_005427.

[0338] As used herein, "ERC1" refers to a gene encoding ERC1 mRNA or polypeptide. The ERC1 gene encodes a coiled-coil domain-containing 6 protein. ERC1 is also known as Cast2, ELKS, ERC-1, and RAB6IP2. In some embodiments, the ERC1 gene is human ERC1. An exemplary ERC1 gene is represented by NCBI gene ID number 23085. An exemplary ERC1 mRNA sequence is represented by NCBI reference sequence NM_178039. An exemplary amino acid sequence of an ERC1 polypeptide is represented by NCBI reference sequence NP_829883.

[0339] As used herein, "KIAA1217" refers to a gene encoding KIAA1217 mRNA or polypeptide. The KIAA1217 gene encodes the KIAA1217 protein. KIAA1217 is also known as ETL4 and SKT. In some embodiments, the KIAA1217 gene is human KIAA1217. An exemplary KIAA1217 gene is represented by NCBI gene ID number 56243. An exemplary KIAA1217 mRNA sequence is represented by NCBI reference sequence NM_019590. An exemplary amino acid sequence of the KIAA1217 polypeptide is represented by NCBI reference sequence NP_062536.

[0340] As used herein, "KIF5B" refers to a gene encoding KIF5B mRNA or polypeptide. The KIF5B gene encodes the kinesin family member 5B protein. KIF5B is also known as HEL-S-61, KINH, KNS, KNS1, and UKHC. In some embodiments, the KIF5B gene is human KIF5B. An exemplary KIF5B gene is represented by NCBI gene ID number 3799. An exemplary KIF5B mRNA sequence is represented by NCBI reference sequence NM_004521. An exemplary amino acid sequence of a KIF5B polypeptide is represented by NCBI reference sequence NP_004512.

[0341] As used herein, "TRIM24" refers to a gene encoding a TRIM24 mRNA or polypeptide. The TRIM24 gene encodes a tripartite motif-containing 24 protein. TRIM24 is also known as PTC6, TF1A, TIF1, RNF82, TIF1A, hTIF1, and TIF1ALPHA. In some embodiments, the TRIM24 gene is a human TRIM24 gene. An exemplary TRIM24 gene is represented by NCBI Gene ID number 8805. An exemplary TRIM24 mRNA sequence is represented by NCBI Reference Sequence NM_003852. An exemplary amino acid sequence of a TRIM24 polypeptide is represented by NCBI Reference Sequence NP_003843.

[0342] As used herein, "VCL" refers to a gene encoding a VCL mRNA or polypeptide. The VCL gene encodes the vinculin protein. VCL is also known as CMD1W, CMH15, HEL114, MV, and MVCL. In some embodiments, the VCL gene is a human VCL gene. An exemplary VCL gene is represented by NCBI gene ID number 7414. An exemplary VCL mRNA sequence is represented by NCBI reference sequence NM_003373. An exemplary amino acid sequence of a VCL polypeptide is represented by NCBI reference sequence NP_003364.

[0343] In some aspects, provided herein are ROS1 fusion nucleic acid molecules comprising at least a portion of ROS1 and at least a portion of another gene.

[0344] In some embodiments, a ROS1 fusion nucleic acid molecule comprises at least a portion of ROS1 and at least a portion of ABR, ASCC3, ELOVL4, QKI, REV3L, MED23, SLC30A8, SLC38A11, TLN1, SLC26A2, SYNGR1, EZR, GOPC, MYO5C, TPD52L1, or TRPC6. For example, in some embodiments, the ROS1 fusion nucleic acid molecule is selected from ROS1-ABR, ROS1-ASCC3, ROS1-ELOVL4, ROS1-QKI, ROS1-REV3L, MED23-ROS1, SLC30A8-ROS1, SLC38A11-ROS1, TLN1-ROS1, ROS1-SLC26A2, ROS1-SYNGR1, ROS1-TRPC6, EZR-ROS1, GOPC-ROS1, MYO5C-ROS1, or ROS1-TPD52L1, with the gene order being from 5' to 3'. Exemplary, non-limiting ROS1 fusion nucleic acid molecules are described herein, and / or in Tables 1-6, and / or in the Examples herein.

[0345] As used herein, "ABR" refers to a gene encoding an ABR mRNA or polypeptide. The ABR gene encodes an ABR activator protein of RhoGEF and GTPase. ABR is also known as MDB. In some embodiments, the ABR gene is a human ABR gene. An exemplary ABR gene is represented by NCBI Gene ID number 29. An exemplary ABR mRNA sequence is represented by NCBI Reference Sequence NM_001092. An exemplary amino acid sequence of an ABR polypeptide is represented by NCBI Reference Sequence NP_001083.

[0346] As used herein, "ASCC3" refers to a gene encoding ASCC3 mRNA or polypeptide. The ASCC3 gene encodes the activating signal cointegrator 1 complex subunit 3 protein. ASCC3 is also known as ASC1p200, HELIC1, and RNAH. In some embodiments, the ASCC3 gene is a human ASCC3 gene. An exemplary ASCC3 gene is represented by NCBI gene ID number 10973. An exemplary ASCC3 mRNA sequence is represented by NCBI reference sequence NM_006828. An exemplary amino acid sequence of an ASCC3 polypeptide is represented by NCBI reference sequence NP_006819.

[0347] As used herein, "ELOVL4" refers to a gene encoding an ELOVL4 mRNA or polypeptide. The ELOVL4 gene encodes the ELOVL fatty acid elongase 4 protein. ELOVL4 is also known as ADMD, CT118, ISQMR, SCA34, STGD2, and STGD3. In some embodiments, the ELOVL4 gene is a human ELOVL4 gene. An exemplary ELOVL4 gene is represented by NCBI Gene ID number 6785. An exemplary ELOVL4 mRNA sequence is represented by NCBI Reference Sequence NM_022726. An exemplary amino acid sequence of an ELOVL4 polypeptide is represented by NCBI Reference Sequence NP_073563.

[0348] As used herein, "QKI" refers to a gene encoding a QKI mRNA or polypeptide. The QKI gene encodes a QKI KH domain-containing RNA-binding protein. QKI is also known as Hqk, QK, QK1, QK3, and hqkI. In some embodiments, the QKI gene is a human QKI gene. An exemplary QKI gene is represented by NCBI gene ID number 9444. An exemplary QKI mRNA sequence is represented by NCBI reference sequence NM_006775. An exemplary amino acid sequence of a QKI polypeptide is represented by NCBI reference sequence NP_006766.

[0349] As used herein, "REV3L" refers to a gene encoding a REV3L mRNA or polypeptide. The REV3L gene encodes a REV3-like DNA-directed polymerase zeta catalytic subunit protein. REV3L is also known as POLZ and REV3. In some embodiments, the REV3L gene is a human REV3L gene. An exemplary REV3L gene is represented by NCBI Gene ID number 5980. An exemplary REV3L mRNA sequence is represented by NCBI Reference Sequence NM_002912. An exemplary amino acid sequence of a REV3L polypeptide is represented by NCBI Reference Sequence NP_002903.

[0350] As used herein, "MED23" refers to a gene encoding MED23 mRNA or polypeptide. The MED23 gene encodes a MED23-like DNA-directed polymerase zeta catalytic subunit protein. MED23 is also known as ARC130, CRSP130, CRSP133, CRSP3, DRIP130, MRT18, SUR-2, and SUR2. In some embodiments, the MED23 gene is a human MED23 gene. An exemplary MED23 gene is represented by NCBI Gene ID number 9439. An exemplary MED23 mRNA sequence is represented by NCBI Reference Sequence NM_004830. An exemplary amino acid sequence of a MED23 polypeptide is represented by NCBI Reference Sequence NP_004821.

[0351] As used herein, "SLC30A8" refers to a gene encoding SLC30A8 mRNA or polypeptide. The SLC30A8 gene encodes a solute transporter family 30 member 8 protein. SLC30A8 is also known as ZNT8 and ZnT-8. In some embodiments, the SLC30A8 gene is a human SLC30A8 gene. An exemplary SLC30A8 gene is represented by NCBI gene ID number 169026. An exemplary SLC30A8 mRNA sequence is represented by NCBI reference sequence NM_001172811. An exemplary amino acid sequence of an SLC30A8 polypeptide is represented by NCBI reference sequence NP_001166282.

[0352] As used herein, "SLC38A11" refers to a gene encoding SLC38A11 mRNA or polypeptide. The SLC38A11 gene encodes a solute carrier family 38 member 11 protein. SLC38A11 is also known as AVT2. In some embodiments, the SLC38A11 gene is a human SLC38A11 gene. An exemplary SLC38A11 gene is represented by NCBI gene ID number 151258. An exemplary SLC38A11 mRNA sequence is represented by NCBI reference sequence NM_173512. An exemplary amino acid sequence of a SLC38A11 polypeptide is represented by NCBI reference sequence NP_775783.

[0353] As used herein, "TLN1" refers to a gene encoding TLN1 mRNA or polypeptide. The TLN1 gene encodes the talin 1 protein. TLN1 is also known as ILWEQ, TLN, and talin-1. In some embodiments, the TLN1 gene is a human TLN1...

Claims

1. A method for detecting a fusion nucleic acid molecule or a fusion polypeptide, comprising detecting a fusion nucleic acid molecule or a fusion polypeptide encoded by said fusion nucleic acid molecule in a sample from an individual with cancer; (a) the fusion nucleic acid molecule is a fusion nucleic acid molecule of ROS1, ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, or RET listed in Table 1; or (b) the fusion nucleic acid molecule is a fusion nucleic acid molecule of ROS1, ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, or RET listed in Table 2, and the cancer is a cancer corresponding to the fusion nucleic acid molecule of ROS1, ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, or RET listed in Table 2; Optionally, the fusion nucleic acid molecule is a ROS1 fusion nucleic acid molecule listed in any of Tables 1-6.

2. The sample contains a plurality of nucleic acid molecules, and detecting the fusion nucleic acid molecule is (a) preparing a nucleic acid sequencing library from the plurality of nucleic acid molecules in the sample; (b) amplifying the library; (c) selectively enriching one or more nucleic acid molecules comprising a nucleotide sequence corresponding to the fusion nucleic acid molecule in the library to produce an enriched sample; (d) sequencing the enriched sample, thereby generating a plurality of sequence reads; (e) analyzing the plurality of sequence reads for the presence of the fusion nucleic acid molecule; (f) detecting the presence or absence of the fusion nucleic acid molecule in the sample from the individual based on the analyzing step; The method of claim 1 , comprising:

3. the plurality of nucleic acid molecules comprises a mixture of cancer nucleic acid molecules and non-cancer nucleic acid molecules, and optionally (i) the cancer nucleic acid molecule is derived from a tumor portion of a heterogeneous tissue biopsy sample and the non-cancer nucleic acid molecule is derived from a normal portion of the heterogeneous tissue biopsy sample; or (ii) the sample comprises a liquid biopsy sample, wherein the cancer nucleic acid molecule is derived from a circulating tumor DNA (ctDNA) fraction of the liquid biopsy sample, and the non-cancer nucleic acid molecule is derived from a non-tumor and / or cell-free DNA (cfDNA) fraction of the liquid biopsy sample. The method of claim 2.

4. A kit for use in a method of treating or slowing the progression of cancer, said method comprising administering to an individual an anti-cancer therapy, said kit comprising: (a) detecting in a sample obtained from the individual a fusion nucleic acid molecule of ROS1, ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, or RET listed in Table 1, or a fragment thereof comprising a breakpoint or fusion junction, or a fusion polypeptide encoded by said fusion nucleic acid molecule; or (b) detecting a ROS1, ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, or RET fusion nucleic acid molecule listed in Table 2, or a fragment thereof comprising a breakpoint or fusion junction, or a fusion polypeptide encoded by said fusion nucleic acid molecule, in a sample obtained from said individual, wherein said individual has a cancer corresponding to said ROS1, ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, or RET fusion nucleic acid molecule listed in Table 2; and Optionally, the fusion nucleic acid molecule is a ROS1 fusion nucleic acid molecule listed in any of Tables 1-6. kit. (a) the fusion nucleic acid molecule is a ROS1 fusion nucleic acid molecule listed in Table 1, comprising or resulting from breakpoint 1 and / or breakpoint 2 corresponding to the ROS1 fusion nucleic acid molecule listed in Table 3; or (b) the fusion nucleic acid molecule is a ROS1 fusion nucleic acid molecule listed in Table 2, the cancer is a cancer corresponding to the ROS1 fusion nucleic acid molecule listed in Table 2, and the fusion nucleic acid molecule comprises or results from breakpoint 1 and / or breakpoint 2 corresponding to the ROS1 fusion nucleic acid molecule listed in Table 6; Optionally, the ROS1 fusion nucleic acid molecule encodes a ROS1 fusion polypeptide comprising a ROS1 kinase domain, or a fragment of a ROS1 kinase domain that has ROS1 kinase activity; optionally, the ROS1 kinase activity is constitutive. The method of claim 1 or the kit of claim 4.

6. The fusion nucleic acid molecule is a ROS1 fusion nucleic acid molecule listed in Table 1, and the cancer is B-cell cancer, melanoma, breast cancer, lung cancer, bronchial cancer, colorectal cancer, prostate cancer, pancreatic cancer, stomach cancer, ovarian cancer, urinary bladder cancer, brain cancer, central nervous system cancer, peripheral nervous system cancer, esophageal cancer, cervical cancer, uterine cancer, endometrial cancer, oral cancer, pharyngeal cancer, liver cancer, kidney cancer, testicular cancer, biliary tract cancer, small intestine cancer, appendix cancer, salivary gland cancer, thyroid cancer, or the like. cancer), adrenal cancer, osteosarcoma, chondrosarcoma, cancer of the blood tissue, adenocarcinoma, inflammatory myofibroblastic tumor, gastrointestinal stromal tumor (GIST), colon cancer, multiple myeloma (MM), myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), polycythemia vera, Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL ), soft tissue sarcoma, fibrosarcoma, myxosarcoma, liposarcoma, osteosarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovium, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, medullary carcinoma, bronchogenic lung carcinoma, renal cell carcinoma, hepatocellular carcinoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, bladder cancer carcinoma), epithelial cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, retinoblastoma, follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, hepatocellular carcinoma, thyroid cancer, gastric cancer, head and neck cancer, small cell carcinoma, essential thrombocythemia, primary myelofibrosis, hypereosinophilic syndrome, systemic mastocytosis, familial hypereosinophilia, chronic eosinophilic leukemia, neuroendocrine cancer, or carcinoid tumor; Optionally, the ROS1 fusion nucleic acid molecule encodes a ROS1 fusion polypeptide comprising a ROS1 kinase domain or a fragment of a ROS1 kinase domain that has ROS1 kinase activity; and optionally, the ROS1 kinase activity is constitutive. The method of claim 1 or the kit of claim 4.

7. 10. The method of claim 1 or the kit of claim 4, wherein the fusion nucleic acid molecule is a ROS1 fusion nucleic acid molecule listed in any of Tables 1-6, and the method further comprises detecting the presence of a mutation in the PIK3CA gene in a sample from the individual, optionally wherein the mutation results in an E545K amino acid substitution in the encoded PIK3CA polypeptide.

8. The kit of claim 4, wherein the fusion nucleic acid molecule is a ROS1 fusion nucleic acid molecule listed in any of Tables 1-6, and the anti-cancer therapy is a ROS1-targeted therapy; optionally, the ROS1-targeted therapy is a small molecule inhibitor, an antibody, a cell therapy, a nucleic acid, a viral-based therapy, an antibody-drug conjugate, a recombinant protein, a fusion protein, a natural compound, a peptide, a proteolysis-directed chimera (PROTAC), a treatment for a ROS1-rearranged cancer, a ROS1-targeted therapy being tested in a clinical trial, a treatment for a ROS1-rearranged cancer being tested in a clinical trial, or any combination thereof.

9. The ROS1 targeted therapy is a kinase inhibitor, optionally a tyrosine kinase inhibitor, a multikinase inhibitor, or a ROS1-specific inhibitor; 9. The kit of claim 8, optionally wherein the ROS1-targeted therapy comprises one or more of crizotinib, lorlatinib, TQ-B3139, repotrectinib (TPX-0005), brigitinib, cabozantinib, ceritinib, or entrectinib.

10. (a) the sample comprises a tissue biopsy sample, a liquid biopsy sample, or a normal control, optionally, the sample is from a tumor biopsy, a tumor specimen, or circulating tumor cells; and / or (b) the sample is a liquid biopsy sample and comprises blood, plasma, cerebrospinal fluid, sputum, stool, urine, or saliva, optionally wherein the sample is a liquid biopsy sample and comprises circulating tumor cells (CTCs), cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), or any combination thereof; and / or (c) the sample comprises cells and / or nucleic acids from the cancer, optionally the sample comprises mRNA, DNA, circulating tumor DNA (ctDNA), cell-free DNA, or cell-free RNA from the cancer; The method of claim 1 or the kit of claim 4.

11. The detecting comprises detecting a fragment of the fusion nucleic acid molecule comprising a breakpoint or fusion junction; Optionally, the fusion nucleic acid molecule is detected in the sample by one or more of a nucleic acid hybridization assay, an amplification-based assay, a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay, real-time PCR, a screening assay, fluorescent in situ hybridization (FISH), spectral karyotyping, multicolor FISH (mFISH), comparative genomic hybridization, in situ hybridization, sequence-specific priming (SSP) PCR, high performance liquid chromatography (HPLC), mass spectrometry genotyping, or sequencing; Optionally, the sequencing comprises a massively parallel sequencing (MPS) technique, whole genome sequencing (WGS), whole exome sequencing, targeted sequencing, direct sequencing, or Sanger sequencing technique; and Optionally, the massively parallel sequencing (MPS) technique comprises next generation sequencing (NGS). The method of claim 1 or the kit of claim 4.

12. The method further comprises selectively enriching one or more nucleic acids in the sample comprising a nucleotide sequence corresponding to the fusion nucleic acid molecule, wherein the selective enriching produces an enriched sample, and optionally, the selective enriching comprises: (a) combining one or more bait molecules with the sample, thereby hybridizing the one or more bait molecules to one or more nucleic acids in the sample comprising a nucleotide sequence corresponding to the fusion nucleic acid molecule to produce nucleic acid hybrids; and (b) isolating the nucleic acid hybrids to produce the enriched sample; Optionally, the one or more bait molecules comprise a capture nucleic acid molecule configured to hybridize to a nucleotide sequence corresponding to the fusion nucleic acid molecule; and Optionally, the capture nucleic acid molecule comprises about 10 to about 30 nucleotides, about 50 to about 1000 nucleotides, about 100 to about 500 nucleotides, about 100 to about 300 nucleotides, or about 100 to about 200 nucleotides, optionally, the capture nucleic acid molecule comprises a DNA, RNA, or mixed DNA / RNA molecule; Optionally, the one or more bait molecules are conjugated to an affinity reagent or a detection reagent, and optionally, the affinity reagent is an antibody, an antibody fragment, or biotin, or the detection reagent is a fluorescent marker; optionally, the selectively enriching comprises using polymerase chain reaction (PCR) to amplify the one or more nucleic acids comprising a nucleotide sequence corresponding to the fusion nucleic acid molecule to produce an enriched sample; and optionally further comprises sequencing the enriched sample. The method of claim 1 or the kit of claim 4.

13. 10. The method of claim 1 or the kit of claim 4, wherein the individual is a human.

14. The method of claim 1 or the kit of claim 4, wherein the cancer is lung cancer, optionally lung adenocarcinoma or non-small cell lung cancer (NSCLC).

15. (i) for detecting a fusion nucleic acid molecule of ROS1, ALK, BRAF, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, MET, RAF1, or RET listed in any of Tables 1 and 3-5, or a fragment thereof including a breakpoint or fusion junction; or (ii) for detecting a ROS1, ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, or RET fusion nucleic acid molecule listed in Table 2 or 6, or a fragment thereof including a breakpoint or fusion junction, in a sample from an individual having a cancer corresponding to said ROS1, ALK, BRAF, ERBB2, FGFR1, FGFR2, FGFR3, MET, NTRK1, RAF1, or RET fusion nucleic acid molecule listed in Table 2 or 6; In vitro use of one or more oligonucleotides.

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