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(12) Patent Application Publication (10) Pub. No.: US 2016/0312305 A1 KENNEDY Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2016/0312305 A1 KENNEDY Et Al US 2016.0312305A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0312305 A1 KENNEDY et al. (43) Pub. Date: Oct. 27, 2016 (54) METHODS AND COMPOSITIONS OF (60) Provisional application No. 61/199,585, filed on Nov. MOLECULAR PROFLING FOR DISEASE 17, 2008, provisional application No. 61/270.812, DAGNOSTICS filed on Jul. 13, 2009. (71) Applicant: VERACYTE, INC., South San Francisco, CA (US) Publication Classification (72) Inventors: Giulia C. KENNEDY, San Francisco, (51) Int. Cl. CA (US); Bonnie H. ANDERSON, CI2O I/68 (2006.01) Half Moon Bay, CA (US); Darya I. G06F 9/20 (2006.01) CHUDOVA, San Jose, CA (US); Eric (52) U.S. Cl. T. WANG, Milpitas, CA (US); Hui CPC ............. CI2O 1/6886 (2013.01); G06F 19/20 WANG, San Bruno, CA (US); (2013.01); C12O 2600/158 (2013.01); C12O Moraima PAGAN, San Francisco, CA 2600/178 (2013.01); C12O 2600/112 (2013.01) (US); Nusrat RABBEE, South San Francisco, CA (US); Jonathan I. WILDE, Burlingame, CA (US) (57) ABSTRACT (21) Appl. No.: 15/164,217 The present invention relates to compositions, kits, and (22) Filed: May 25, 2016 methods for molecular profiling and cancer diagnostics, including but not limited to gene expression product mark Related U.S. Application Data ers, alternative exon usage markers, and DNA polymor (63) Continuation of application No. 13/589,022, filed on phisms associated with cancer. In particular, the present Aug. 17, 2012, which is a continuation of application invention provides molecular profiles associated with thy No. 12/592,065, filed on Nov. 17, 2009, now Pat. No. roid cancer, methods of determining molecular profiles, and 8,541,170. methods of analyzing results to provide a diagnosis. Patent Application Publication Oct. 27, 2016 Sheet 1 of 111 US 2016/0312305 A1 Input CEL File Pathology 151329HUEX1A1 CEL Beni 151345HUEX1All-CEL Benign 1S326HUEXAICEL Benign 1538OHUEX1A, CEL Benign 151289HUEX1A11CEL Benign 51338HUEX1A11CEL Benign 151315HUEX1A1 CEL Benign 151306HUEX1A11CEL Benign 151316HUEX1A11CEL Benign 151276HUEXA11CEL Benign 15130SHUEX1A11CEL Benign 151330HUEX1A11CEL B 151336HUEX1A11CEL 51275HUEXA11CEL 151309HUEX1A11CEL Benign 151284HUEXA CEL B e 3. 151295HUEX1A11CEL Benign 151279HUEX1A1 CEL Beni gn 15293HUEX1A11CEL S1359HUEXA CEL 15.325HUEXA1CEL 15283HUEX1A1 CEL Benign 151361HUEX1A, CEL Benign 15294HUEXA1 CEL . B gn : 151373HUEX1A11. CEL B enign 151364HUEX1A11CEL 1S1308HUEX1A11CEL 151291HUEX1A11CEL B 1.gn 15128SHUEXA11CEL B enign 15363HUEXA.CEL Malignant 151347HUEX1A1 CEL Malignant Figure 1 Patent Application Publication Oct. 27, 2016 Sheet 3 of 111 US 2016/0312305 A1 Normal Figure 1 Continued Patent Application Publication Oct. 27, 2016 Sheet 4 of 111 US 2016/0312305 A1 Gene DE FDR Fold-change Fold-change Fold-change p-value DE Malignant? Malignant/ Benign/ p-value Benign Normal Normal -2.45 -2.32 -2.23 -2.07 -3.36 -1.74 -92 -1.65 2.42 1.43 -2.42 -1.25 -2.32 -1.13 -1.78 MAN2 203E-08 126E-05 -19 -312 -1.63 ANGPTL1 353E-08 188E-05 | 1.44 -200 - 39 TBX22 9.39E-08 1.61 -2.43 105E-07 2.10 1.25 145E-07 -3.18 -4.29 -135 TSC22D 61E-07 1.37 -1.38 77E-07 -65 -3.06 -1.85 83E-07 4.76 -2.8 259E-07 1.82 2.08 SLC26A4 2.80E-07 3.22 -427 -1.33 ADH1B 2.91E-07 8.84E-05 -1.36 -2.56 4.32E-07 1.15E-04 180 3.16 1.76 Figure 2 Patent Application Publication Oct. 27, 2016 Sheet 5 of 111 US 2016/0312305 A1 GABRB2 4.40E-07 2.45 2.60 DPP6 5.04E-07 1.23E-04 -1.53 -2.45 -1.87 -129 8 1.95 -1.09 F 103E-06 2.10E-04 -1.93 - S6 EPHA -1.20 -2.11 -1.75 -2.04 -1.16 -2.50 -1.45 -2.08 -1.82 -3,28 -1.32 2.03E-06 3.29E-04 -2.14 -2.07 1.03 IP 2.37E-06 3,64E-04 2.22 1.23 2.72E-06 4,06E-04 -1.42 -2.17 -153 2.79E-06 4.11E-04 1.94 2.43 26 3.34E-06 4,61E-04 -1.54 3.07 24. 4.05E-06 5.29E-04 1.91 5.27E-04 1.34 :f73 4.44E-06 5.56E-04 1.87 2.05 1.09 SF11B -1.73 AMK2N1LO 2.92 2.23 -1.31 S 3 s 2.81 3.30 OGN -1.21 -2.05 -1.69 1.86 -2.64 : -95 CRAB Pl -6.83 2.43 E. ITGA2 1.36E-OS 1.23E-03 1,73 2.20 1.27 DUSP1 156E-05 1.36E-03 -133 -2.28 -1.72 Figure 2 Continued Patent Application Publication Oct. 27, 2016 Sheet 6 of 111 US 2016/0312305 A1 EGR 1.78E-0S -1.30 -1.97 EGR2 2.03E-05 -1.75 - 1.93 SORBS2 2.15E-05 -1.67 -1.23 MET 2.21 E-05 2.09 1.11 CLDN16 2.27E-05 2.48 w PSD3 2.76E-05 1.76 1.21 3.17E-05 -1.97 1.02 2.10 144 201| 139 PKHD1 L, 59E-05 -2.5S 1.50 6,09E-05 -1.8 -1.12 7.93E-OS 1.78 1.15 1.06E-04 1.43 1.33 1.10E-04 -1.77 -1.32 1.3OE-04 58 l.24 sODOw 4i. WDR72 147E-04 -92 -1.31 MT1G 153E-04 6,55E-03 -2,49 -1.23 56E-04 6.65E-03 -0.6 4.95 ZNF 804B 1,62E-04 6,8SE-03 -1.20 -1.85 CTGF 1.64E-04 6.86E-03 -1.92 -1.48 RHOBTB3 1.65E-04 6.90E-03 1.18 1.65E-04 6.86E-03 -1.31 -1.62 Figure 2 Continued Patent Application Publication Oct. 27, 2016 Sheet 7 of 111 US 2016/0312305 A1 SERPINA 1.65E-04 6.87E-03 Figure 2 Continued Patent Application Publication Oct. 27, 2016 Sheet 8 of 111 US 2016/0312305 A1 Alt. Exon Gene p-value RHOBTB3 S1B CENPJ ABCA1 0.00E+00 O O.OOE-00 OOOE-00 P L1 SGRP3 OOOE-00 T O.OOE-00 AFAP 0.00Etoo 0.00E00 C MFSD11 s EFTUD1 O.OOE-00 Figure 3 Patent Application Publication Oct. 27, 2016 Sheet 10 of 111 US 2016/0312305 A1 KCTD10 102E-244 104E-242 DIO | 111E-232 1.03E-230 PER2 | 1.5SE-22 | 1.47E-226 SLC39A9 FLU215 A ETV CPEB2 Figure 3 Continued Patent Application Publication Oct. 27, 2016 Sheet 11 of 111 US 2016/0312305 A1 PKHDL1 3.58E-76 2.52E-174 5.54E-76 3.88E-174 ZW10 3.17 E-175 2.21E-173 Figure 3 Continued Patent Application Publication Oct. 27, 2016 Sheet 12 of 111 US 2016/0312305 A1 Ge e DE FDR p-value DE p-value D 3.82E-04 3.S1 4.15E-04 -1482 4.15E-04 4.97 FN1FN 1. |957E08 4.5E-04 10.71 KITKIT 135E-07 4.43E-04 4.75 EPS8 157E07 4.44E04 3.1 S 4.61E-04 5.09 IHP 4.72E-04 -3.06 TCD 2526.806 2,08E-07 4.8OE-04 2.86 MYEF2 4.8OE-04 3.61 2.32E-07 4.89 -2.84 5.56E-04 -4.49 S.S6E-04 4, 13 6.53E-04 428 7.72E-04 -5.28 7.72E-04 3.77 8.86E-04 -4.26 GALE 9. 19-04 3.46 GABRB2 1.03E-03 10,65 3 1.22E-03 6.67 .. NT7 1.22E-03 3.78 CYSLTR2 2.53E-06 1.56E-03 740 RA 3.49E-06 | 1.89E-03 -9.03 PSD3 4.08E-06 2.04E-03 FABP4 4.18E-06 2.04E-03 -1.06 MATN2 4.23E-06 2.05E-03 2.87 Figure 4 Patent Application Publication Oct. 27, 2016 Sheet 13 of 111 US 2016/0312305 A1 4.78E-06 2.1 TE-03 -4.40440 2.99E-03 3,06E-03 9.12E-06 3.22E-03 LRRC7 9.97E-06 3.38E-03 SPINKS 3.53E-03 6.08 P S.26E-03 -4.85 S.28E-03 3.11 MRO 2.17E-05 5.45E-03 -3.35 D 2.45E-05 5.93E-03 -3.38 TUSC3 2.58E-05 6.13E-03 4.30 TFF3TFF 3 2.65E-0526SE-OS 621E-036.2E-03 -5,4-54s TNFRSF10C 2.78E-05 6.38E-03 2.85 PROS1 2.80E-05 6.40E-03 2.72 CD 3430620 2.91 E-05 6.55E-03 3.96 GPM6A 3.10E-05 6.80E-03 -3.86 CDON 3.28E-05 7.05E-03 -2.73 Figure 4 Continued Patent Application Publication Oct. 27, 2016 Sheet 14 of 111 US 2016/0312305 A1 7.75E-03 4.02 7.90E-03 -2.71 ADAMTS9 7.91E-03 2.8S 8.33E-03 2.81. LONRF2 8.4SE-03 3.73 8.54E-03 3.08 TPARP 8.72E-03 2.76 456E-054.56E-05 8.73E-03 -3.90 4.7OE-05 8.89E-03 12.09 TMEMOO 4.7147E-05 E-05 8.90E-03 4.37 4.75E-05 8.93E-03 -3.76 N1 4.76E-OS 8.93E-03 7.83 4.8OE-05 8.97E-03 3.09 4.82E-05 9.00E-03 3.46 AMD4A 5.00E-05 9.21E-03 2.80 KHD1 L1 S.21E-05 9.49E-03 -7.2 MET 5.26E-05 9.55E-03 3.0 FAM114A1 5.3OE-05 9,60E-03 2.79 SCEL 5.53E05 9.85E-03 1.7 SLA 1.22E-04 | 1.58E-02 -2.99 RMS2 2.01 E-04 2.13E-02 2.97 0408 2.44E-04 2.38E-02 2.75 RAP 2.5OE-04 2.42E-02 2.74 AM20A 3.18E-02 2.98 PHF16 Figure 4 Continued Patent Application Publication Oct.
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