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WO 2014/172046 A9 O (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) CORRECTED VERSION (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2014/172046 A9 23 October 2014 (23.10.2014) P C T (51) International Patent Classification: 61/824,253 16 May 2013 (16.05.2013) US C12Q 1/68 (2006.01) G06F 19/20 (201 1.01) 61/860,1 15 30 July 201 3 (30.07.2013) US 61/907,939 22 November 2013 (22. 11.2013) us (21) International Application Number: 61/915,392 12 December 2013 (12. 12.2013) us PCT/US2014/029592 61/935,650 4 February 2014 (04.02.2014) us (22) International Filing Date: 61/940,226 14 February 2014 (14.02.2014) us 14 March 2014 (14.03.2014) (71) Applicant: LIFE TECHNOLOGIES CORPORATION (25) Filing Language: English [US/US]; Legal Department, Intellectual Property, 5791 Van Allen Way, Carlsbad, California 92008 (US). (26) Publication Language: English (72) Inventors: RHODES, Daniel; Life Technologies Corpora (30) Priority Data: tion, Legal Department, Intellectual Property, 5791 Van 61/813,182 17 April 2013 (17.04.2013) Allen Way, Carlsbad, California 92008 (US). SADIS, 61/813,465 18 April 2013 (18.04.2013) Seth; Life Technologies Corporation, Legal Department, [Continued on nextpage] (54) Title: GENE FUSIONS AND GENE VARIANTS ASSOCIATED WITH CANCER (57) Abstract: The disclosure provides gene fusions, gene variants, and novel as sociations with disease states, as well as kits, probes, and methods of using the same. raw cells Annotate and Filter Fusions 424K annotated fusion cells Summarize and Prioritize Fusions Gene Fusion RNASeq data < processing workflow o w o 2014/172046 A 9 1I II II I III IIII II 11lll l ll III! Ill III II Intellectual Property, 5791 Van Allen Way, Carlsbad, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, California 92008 (US). WYNGAARD, Peter; Life Tech¬ NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, nologies Corporation, Legal Department, Intellectual RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, Property, 5791 Van Allen Way, Carlsbad, California TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, 92008 (US). KHAZANOV, Nikolay; Life Technologies VN, ZA, ZM, ZW. Corporation, Legal Department, Intellectual Property, (84) Designated States (unless otherwise indicated, for every 5791 Van Allen Way, Carlsbad, California 92008 (US). kind of regional protection available): ARIPO (BW, GH, BANDLA, Santhoshi; Life Technologies Corporation, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, Legal Department, Intellectual Property, 5791 Van Allen UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, Way, Carlsbad, California 92008 (US). TOMILO, Mark; TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, Life Technologies Corporation, Legal Department, Intel¬ EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, LU, lectual Property, 5791 Van Allen Way, Carlsbad, Califor¬ LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, nia 92008 (US). EDDY, Sean; Life Technologies Corpor¬ SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, ation, Legal Department, Intellectual Property, 5791 Van GW, KM, ML, MR, NE, SN, TD, TG). Allen Way, Carlsbad, California 92008 (US). BOWDEN, Emma; Life Technologies Corporation, Legal Depart¬ Declarations under Rule 4.17: ment, Intellectual Property, 5791 Van Allen Way, Carls¬ — of inventorship (Rule 4.17(iv)) bad, California 92008 (US). Published: (74) Agent: DUKE, Jennifer; Life Technologies Corporation, Legal Department, Intellectual Property, 5791 Van Allen — with international search report (Art. 21(3)) Way, Carlsbad, California 92008 (US). (88) Date of publication of the international search report: (81) Designated States (unless otherwise indicated, for every 18 June 2015 kind of national protection available): AE, AG, AL, AM, (48) Date of publication of this corrected version: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, 2 5 February 2016 BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, (15) Information about Correction: GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, see Notice of 2 5 February 2016 KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, GENE FUSIONS AND GENE VARIANTS ASSOCIATED WITH CANCER FIELD OF THE INVENTION [0001] The present invention relates generally to gene fusions and gene variants that are associated with cancer. BACKGROUND [0002] Aberrations such as chromosomal translocations and gene variants are frequently found in human cancer cells. Chromosomal translocations may result in a chimeric gene expressing a fusion transcript which is then translated into a fusion protein that affects normal regulatory pathways and stimulates cancer cell growth. Gene variants may also result in aberrant proteins that affect normal regulatory pathways. [0003] The identification of new fusion genes, new variants of known fusion genes, and gene variants or alleles provides an opportunity for additional diagnostics and cancer treatment targets. BRIEF SUMMARY OF THE INVENTION [0004] The disclosure provides novel gene fusion variants and gene fusion- disease state associations. The gene fusions provided herein are associated with certain cancers. The disclosure further provides probes, such as amplification primer sets and detection probes, as well as methods and systems of detection, diagnosis, and treatment and kits that include or detect the gene fusions disclosed herein. [0005] In one embodiment, the disclosure provides a reaction mixture comprising a probe or a set of probes that specifically recognize a gene fusion selected from Table 1 - Table 3 , Table 19 , and Table 22. The set of probes can be, for example a set of amplification primers. In another embodiment, provided herein is a reaction mixture that includes a set of primers that flank a gene fusion selected from Table 1 - Table 3 , Table 19, and Table 22 in a target nucleic acid. For example, the set of primers can each bind to a target sequence in the human genome within 1000, 750, 500, 250, 100, 90, 80, 75, 70, 65, 50, or 25 nucleotides of opposite sides of the one of the fusion breakpoints identified in Tables 4-6, 20, and 23. The reaction mixture of this embodiment can further include a detector probe that binds to either side of a breakpoint in a gene fusion selected from Table 1 - Table 3 , Table 19, and Table 22, or that binds a binding region that spans the breakpoint in a gene fusion selected from Table 1 - Table 3 , Table 19, and Table 22, including specific embodiments where the breakpoint is identified in Tables 4-6, 20, and 23. In exemplary embodiments, the detector probe binds to a target sequence in the human genome within 1000, 750, 500, 250, 100, 90, 80, 75, 70, 60, 50, or 25 nucleotides of one of the fusion breakpoints identified in Tables 4-6, 20, and 23. The reaction mixture that includes a detector probe, or does not include a detector probe, can further include a polymerase, a reverse transcriptase, dNTPs, and/or a uracil DNA deglycosylase (UDG). The polymerase, the reverse transcriptase, and the UDG are typically not from human origin. The polymerase in illustrative embodiments is a thermostable polymerase such as a Taq polymerase. In certain embodiments, the dNTPs in the reaction mixture include dUTP, and the reaction mixture can in certain examples, be devoid of dTTP. Furthermore, the reaction mixture can include an amplicon, such as a DNA amplicon that includes one or more deoxyuridine ("dU") residues. In certain embodiments the reaction mixture includes a DNA amplicon that includes one or more dU residues for every deoxythymidine residue in the corresponding human genomic sequence. In certain embodiments, the amplicon includes a segment for which a corresponding sequence is not found in the human genome, such as, for example, a DNA barcode sequence. The non-human segment can be for example, 5-10,000, 5-5000, 5-1 000, 5-500, 5-100, 5-50, 5-25, 5-10, 10- 10,000, 10-5000, 10-1 000, 10-500, 10 -100, 10-50, or 10-25 nucleotides in length. In certain embodiments, the amplicon includes segment that corresponds to the region of the human genome that spans an intron, but the amplicon does not include a segment corresponding to the intron. The reaction mixture can further include a target nucleic acid, for example a human target nucleic acid. The human target nucleic acid can be, for example, isolated from a biological sample from a person suspected of having a cancer selected from: BLCA = bladder carcinoma, BRCA = breast carcinoma, CESC = cervical cell carcinoma, COAD = colon adenocarcinoma, GBM = glioblastoma multiforme, HNSC = head and neck squamous cell carcinoma, KIRK = clear cell renal cell carcinoma, KIRP = kidney renal papillary cell carcinoma, LAML = acute myeloid leukemia, LGG = brain lower grade glioma, LIHC = liver hepatocellular carcinoma, LUAD = lung adenocarcinoma, LUSC = squamous cell lung carcinoma, OV = ovarian serous adenocarcinoma, PRAD = prostate adenocarcinoma, READ = rectal adenocarcinoma, SKCM = cutaneous melanoma, STAD = stomach adenocarcinoma, THCA = thyroid carcinoma, and UCEC = uterine corpus endometrioid carcinoma. In certain embodiments, the target nucleic acid is from a tumor, for example a tumor of one of the cancer types listed in the preceding sentence. [0006] In another embodiment, a set of probes that specifically recognizes a nucleic acid comprising at least one of SEQ ID NOs: 1-257 (gene fusions) is provided. In another embodiment, provided herein is a set of primers that specifically amplify a target nucleic acid that includes at least 25, 30, 40, 50, 75, 100, 125, 150, 200, or all of SEQ ID NOs: 1-257, or that amplifies up to 25, 30, 40, 50, 75, 100, 125, 150, 200, or all of SEQ ID NOs: 1-257.
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