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 B eni 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 CD ON 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. 27, 2016 Sheet 15 of 111 US 2016/0312305 A1

LAMB3

1.34E-03 SULF1

Figure 4 Continued Patent Application Publication Oct. 27, 2016 Sheet 16 of 111 US 2016/0312305 A1

Gene DE FOR

Int/Norm Normal

PLA2R1 -1.74 MYE F2 1.43 -1.25 I 2 -1, 13 KHDRBS2 -1.30 FN1 102E-05 || 702E-127 396 1.47 SPATS2 2.79E-04 56 1.38 -1.12 MATN2 -1.63 -147 ChCGn -2.99 -1.32 -39 -1.63 1.36 TP -4.29 -13S 5.96B-OS 5.75E43 -1.19 -1.42 -1.38 AL 1.14 GCC -1.33 TR2 1.67 -1.05

NRCAM 1.76 AD H 1C -1.43

RB248

-1.60 -1.34

-1.46 -1.16 E.CX3 2.28E-04 1.68 1.12 Figure 5 Patent Application Publication Oct. 27, 2016 Sheet 17 of 111 US 2016/0312305 A1

UNX Tl E-04 E-04 3.64E04 S2E-19 139 161 | 1.16 3.69E-04 STK32A 4.12E-04 3.12E-12 2.11

3 7 TBC1D GE ISIE 6 to 45 7.70E-04 ELMO1 8,04E-04

P 9.39E-04 || 1.03E-O -1.67 2.64 -158 FAM20A 9.45E-04 144E-127 129 161 125 M ETTL7B 9.7OE-04 MAP2 9.94E-04 CD36 || 104E-03 0.00E00I 203 -19s 104

DCBLD2 | 1.11E-03 1.08E06 1.59 168 1.05

ITG 123E-03 7.15E-200 2.20 1.27 151E-03 5,74E-13 1.97 1.66E-03 4.3OE-04 1.64 3S EGR2EGR2 1.66E-03 5.78E-200 -3.38 -1.93 MET 1.72E-03 4.6SE-09 2.32 1.11

CLDN16 1.74E-03 1.27E-19 3.55 HM 1.78E-11 1.79 1.21 CENPJ 2.13E-03 0.00E-00 -1.12 GPR125 2.17E-03 1.04E-11 167 -17 RAB 2.3E-2 -1.94 1.02 CD63 2.42E-03 7.85E-04 140 160

Figure 5 Continued Patent Application Publication Oct. 27, 2016 Sheet 18 of 111 US 2016/0312305 A1

2.49E-03 3 17 256E-03 3.69E-180 1.56 1.26 -1.28

7A5 07E-1 7 -1.31 -1.68 -129 1.18 1.19 6 1.44 1.39

- -35 ERO1 LB 1 O 331E0331E-03 stria -2.55 -3.84 -.50 -140 -1.12 DEPDC6 -153 -1.10 LRRC7 1.17 -1.21 1. ALD -1.37 SLA. 1.2 LO NRF2 -1.24 SD 3 5.3E-03 1.43 1.33 LIFR 2.95E-17 -1.32 C7orf24 24 S100A2 3.25E. 115 242 139 -1.74 2 -1.31

-1.23 NRF2 LP 6.75E-03 -1.03

6.86E-03 -1.31 -1.62

Figure 5 Continued Patent Application Publication Oct. 27, 2016 Sheet 19 of 111 US 2016/0312305 A1

TMEM171

Figure 5 Continued Patent Application Publication Oct. 27, 2016 Sheet 20 of 111 US 2016/0312305 A1

TCID GENE na29 TCD TCD 2337524 2337524 2501697 ACTR3 2676901 ACTR8 2582562 ACVR1 3415148 ACVR1B 25095.57 ACVR2A 3415109 ACVRL1 2623441 ACY1 3572263 ACYP1 2641232 2641232 3702382 ADAO2 331 1832 ADAM12 252368g AB2 253982 ADAM17 3011492 ADAM22 3927446 ADAMTS1 3641633 ADAMTS17 3368940 3700158 ADAMTS18 2889916 ADAMTS2 3927480 ADAMTS5 3153400 3153400 28596O1 ADAMTS6 2680046 ADAMTS9 3253452. 3253452 264 1341 ACAD9 297,7471 ADAT2 3321980 3321980 2597347 2800711 ADCY2 3398455 3398455 3708.306 ACADV. 3558168 ADCY4. ADCY6 3.153716 ADCY8 377.5908 ADCYAP1 2558736 ADD2 ADD3 2779271 ADH1A 3164312 ACER2 2779231 ADH 1A 2779.199 ADH 1A 27792.71 ADH1B 3443348 A2M 2779231 ADH1B 2558150 AAK 2779.199 ADH1B 2779271 ADH1C 2779231 ADH1C 27791 24 ADH4 2387711 ADH5 2756309 2779095 ADH5 2779163 ADH6 32521.70 3248.824 2375596 ADORA1 OOO1 ADORA2A 3711869 ADORA2B 2427981 ADORA3 3265047 ADRB1 4O498.35 ADRB3 394,0631 ADRBK2 2464353 ADSS

7232 2834957 AFAP1L1 AFAP1L2 2399743 EAFARP1 Figure 6 Patent Application Publication Oct. 27, 2016 Sheet 21 of 111 US 2016/0312305 A1

TCID GENE na29 TCID GENE na29

3554592 AFF1 2740067. ANK2 2875555 AFF4 3169331 ALDH1B1 3290875 ANK3 2533670 AGAP1 3714068 ALDH3A2 ANKOD1A 3337329 ALDH3B1 37.27787. ANKFN1 3379.091 ALDH3B1 3741997

3372420 AGB 2 2849469 ANKH 29.49830 AGER 3349535 ANKK 2530599 AGFG1 3083936 AGPAT5 3778252 ANKRD12 3095.815 AGPAT6 734.047 AGPAT9 O39791 AGR2 O3983O AGR3 695726 AGRP 212728 AGTPBP1 2565559 ANKRD23 647015 AGTR1 28894.868894.86 AGXT2L2 2356273 ANKRD35 023384 AHCYL2

975385 AH1 339,149 AG9 ANKRD36 3 375735 AHNAK 2564816 ANKRD36B 581221 AHNAK2 2565935 ANKRD36B AHR 2488785 ALMS1 54.673 ANKRD37 i AHSA1 2488785 ALMS1P 3146661 ANKRD46 555277 AHSA2 3709417 ALOX15B 3876142 522398 AIDA 324.4622 285,7488 381876 AIDA 2532314 ATP 2916825 ANKRD6 457573 2532294 ALP 2904329 ANKS1AA. 2837 ADA 3467351 191877 AF1 L. 3678279 2532294 ALPP 32.17361 3226138 AK1 2532294 ALPPL2 2532272532272 ALPPL2 323748 2594773 ALS2CR12 722O 2852742 AMACR 774971 1569 3374544337544 AMBRA1AMBRA 286975 3692856 AMFR 174816 3393670393670 AMICA1AMCA1 170 4. 34524782478 AMGO2 O68 27248 NXA2P 292008E.i3 5 724 7 3410322 AMN1 79.0109 ANXA2P1 299 KAP8 3167110 ANXA2P2 30 1 2381 A.KAP9 3249171 ANXA2P3 92O1 KD2 3046.739 AMPH 732844 AKR1B1 2487412 ANXA4 4027 ANXA5 274758 2881747 3046062 743 s 3722195 743 AKR7L 2522247 OO9849 S2 54677 838522 ALDH16A1 3388517 3016177 AP1S1 Figure 6 continued 32223.27787 Patent Application Publication Oct. 27, 2016 Sheet 22 of 111 US 2016/0312305 A1

TCID GENE na29 TCD GENE na29 CID GENEna29 260287 AP S3 3191074 ASB6 2966636 ASCC3 2655476 AP2M1 3429008 ASCL.1 2437417 ASHL 3295032 AP3M1 3094.447 ASH2 3096007 AP3M2 3966597 ASMT 3137.530 ASPH 3214845 ASPN 3352503 ARHGEF12 2695295 ASTE 3593770 AP4E 243780. ARHGEF2 38.81874 ASX 2544925 ASX2 2505833 ARHGEF4 3069399 ASZ1

3029646 ARHGEF5 3299255 IATAD1 3151534 ATAO2 37.16893 IATAD5 3310413 ATE1 3369249 APP 258 8 O66 ATF2 2 379132 ATF3 335615 APLP2 2621827 ARH2 949.622 ATF6B 647827 ATF7P2 2832453 ARL13B 818212 ATG10 769779 ATG12 3578278 ATG2B 383589 APOC 3304475 ARL3 ATG4C 2931391 ARL4A 2526759 ATIC AR4A 254.8776 ATL2 3347658 ATM 3390 143 ATM 367O668. ATMN 2726O72 ATP1OD 2654.855 ATP11B 2711225 ATP13A4 3469319 APPL2 2711205 ATP13A4 3203311 APTX 2353477 ATP1A1 3802396 AQP4 2645764 ATP1B3 3595594 ACP9 3431483 ATP2A2 3617757 AQR 3464983 ATP2B1 3.81241 ARAP1 3321150 ARNTL 2375706 ATP2B4 2765590 ARAP2 ATP2C1 73.542 AREG 2695.295 ATP2C1 3453370 ARF3 3671727 96.2587 ARFGAP3 139035 ARFGEF1 3888055 ARFGEF2 37684.74 ARSG 74.7893 ARFP1 25841 ARG 5246.18 ARGLU1 74.6693 ARHGAP10 283920 ARHGAP12 508611 ARHGAP15 2973694 ARHGAP18. 3153428 ASAP1 3302187 ARHGAP19 2468811 3390641 ARHGAP20 2553262 ASB3 Figure 6 continued Patent Application Publication Oct. 27, 2016 Sheet 23 of 111 US 2016/0312305 A1

TCID GENE na29 GENE na29 TCD 2767378 583014 BAZ2B 325.6074 324,453 BOX1 2523213 O960 BS4 3938817 2996321 BBS9 BNIP1 2634985 BBX 314040 BNIP3 3835777 BCAM 761285 BOD1 BCAP29 58 BOK O26669 BCAP31 683050 729569 BCAS3 593838 3311775 BCCIP 3732448 2696.62 BCCP 2877.257 147 BCDIN3D . 2456849 AURKA 2420808 BCL 10 : URKAPS1 2554975 BC-1 1A 84.2059 65 72 2 BC2 267678 V 36351.98 BCL2A1 0.13730 59722 AVPR1A 2489 BCL2-1 50O275 BCL211 54417 667181 AZ2 36256 BCL2-13 36470 591 AZIN1 5207 BCL2L14 E.645 B3GALNT2 386737 BCL7B 462 B3GALT2 818 BCL9

B3GAT3 348940 BCO2 577277 3824596 B3GNT3 814527 BDP1 2952497 3475511 B3GNT4 75857 BECN1 773.545 3418394 B4GALNT1 411799 77 f 3400236 B4GALNT3 0.16308 BEX1 5533430375684 440664 B4GALT3 O16308 3926080 3908963 B4GALT5 649245 BFAR 2899.372 3120 B4GALT6 899.111 BFSP1 2899298 3110217 BAALC 2608725 BHLHE40 2899.372 3393257 BACE1 8088 HLHE41 2899298 392.1933 BACE2 289.9372 3981120 BAG1 2817251 HM2 2899298 51 92 71 B44859 548 BRBB 3261165 3 772187 BRC5 301.4742 24762.19 BRC6 3764289 893250 BRC7 2690012 Bzw1 3924929 BAGE3 522439 BZW 2690012 17D BZW 11 3286776 223 3303392 BLOC1S2

BAMB 369229 BMF BANK1 32384913323: BMI1 BAT1 308925 BMP1 3259253 C10orf13

BAT2D1

BAT5 2958172 BMP5

BAX

BAZ1A BAZ1B

BAZ2A Figure 6 continued

Patent Application Publication Oct. 27, 2016 Sheet 26 of 111 US 2016/0312305 A1

3025545 CALD1 3933923 CBS 285.5542 CCL28

2551924 CALM2

3599280 CALML4 3259367 CC2D2B 2619480 ICCBP2

3235516 CAMK1D 3686587 CCDC101

3251490 CCDC109A 3294.854 CAMK2G 3380065 2400177 ICAMK2N1

1704

2545999 CCDC121 95.3866

2838.598

32594.00

2884578 2702307

90853 404.1923 4018.194

2612278 3453218 3831168 2507,209 33261.83 36 26491.82 389450 262O73403336351 389353 3.42163O 2423264 CCDC18 820865 CARM1 814693 CARTPT 3928070 7798 CASC1 2913694 26.6583 CASC2 33.16344 590014 CASC5 2432714 301.3178 CASD1 34427O6 CD163 541 CASKIN1 835.035 CD177 38.9450 CASP1 3434193 CCDC64 286O178 CASP1 3655109 3389.257 CASP12 7964.84 CASP3 3389273 CASP4 2636125 CD200

2 781893 CASP6

918952 CASP8AP2

2429.556 CASO2 CCDC76 638824 CASR CCDC80 86 CAST CCDC82 821194 CAST CCDC84 326400 CAT CCDC88A 3 378043816693158 CATSPER1 CCDC90B 825514 CATSPER2 CCDC94 2583254. CD302 CAV1 CCDC96 3020273 CAV2 284.0002002 CCD C99 3293998 CBARA1 2948821 CCHCR CC13 CCL14

222335 CCL15

CC16

CCL19 3326635 CD44 Figure 6 continued Patent Application Publication Oct. 27, 2016 Sheet 27 of 111 US 2016/0312305 A1

CID GENE na29 2773719 CDKL2 392.0003 HAF1B 905169 CDKN1A 34831.59 HCHD2 488 CDKN2B 309.9089 HCHD7 87.1896 CDO1 2356721 HD1 L, 2328463 770 CDON 9138 HD2 4024373 COR1 709244 HD3

684782 054 CHD4 734270 CDS1 906160 CHO6 3669 CEACAM1 CHD9 3834.257 CEACAM21 676854 CHDH 3834379 CEACAM5 3354799 CHEK1 3834341 CEACAM5 3479438 CHFR 3402315 CD9 3834379 CEACAM6 3549092 CHGA 3875179 CHGB CELA2B 2451593 CH31 247399.1 CENPA 335.8538 CHID1 2771654 CENPC1 26O7568 CHL1 2780172 CENPE 4.006841 CHMP5 3505937 CENPJ 2994.835 CHN2 2859667 CENPK 3915569 CHOOL 2444451 CENPL 8080 CHPT1 3221543 CDC26 3.187577 CEP110 342867 CHPT CEP170 4018080 CHRDL1 3864 CEP17OL 3615791 CHRFAM7A

77981.7 CEP.192 3359897 CHRNA10 CEP290 129026 CHRNA2 3.19339 CDC42 2369843 CEP350 391.3775 CHRNA4 58.444 CEP55 CH 5 CEP57 CH RNA SA 46462246.38646 CEPT1

8

3692.701 CES1 2532378 CHRND CES2 CHRNE 2701 2532399 CHRNG CES8 CHST10 26263 CETN2 CHST2 CETP CHST9 2902844 CFB CIAO1 CDEB

CFH CILP 3671202 ICDH13 CFHR1 CISD2 CFHR1 CSH 2373406 CFHR3 Cir 37 CFHR4 CITED1 CF . i. CFLAR 2805078 CDH6 508,696 CGO30 341.7146 867573 3887573 CGB2 3867573 CGB5 3223425 CDK5RAP2 3867573

3621351 CKMT1A 3867573 3178583 CKS2 3482498 CDK8 3817501 Figure 6 continued Patent Application Publication Oct. 27, 2016 Sheet 28 of 111 US 2016/0312305 A1

TCID GENE na29 TCD GENE na29

3 815399 CNN2 245309 COX7C 2345023 CLCA1 2424102 CNN3 27.00244 3260265 CNNM1 31 O6559 CP 26971 CNNM2 264709 CPA3 6 936 7 3 CNOT1 3716411 CPD 3421897 CNOT2 2750627 CPE 3074362 CNO4. 2719.361 CPEB2 2844709 CNO6 284.1699 CPEB4 2774565 CNOT6 296.3859 CNR 3461341 CPM 3105904 CPNE3 2695.453 CPNE4

CPNE8 2524.817 CPO 3158516 CPSF1

2468920 CPSF3 2315739 CPSF3L 3.421446 CPSF6 CPVL 3769969 3895.118 CPXM1 2 377427 CR1 L. 2377.283 CR2 603295 CRABP1 438458 CRABP2

66O648 CRBN 99.455.8 CREB5 677795 CREBBP 3230594. CLIC3 567647 CREG2 301.3054 COL1A2 610136 CRED1 2955556 CLIC5 CRED2 3919278 ICC6 2816536 CRHBP 3860229 CLIP3 2642261 COL29A1 554.818 CRIP2 2475407 CLIP4 2956563 CRISP3 2437329 CLK2 3720228 CRKRS 2437329 CLK2P 3855104 CRLF1 357794O CLMN 27.59038 CRMP1 34945O2 CLNS 2398193 CROCC 3629494 CLPX 2398193 CROCCL1 24O642O CLSPN 3113133 COLEC10 239819.3 CROCCL2 2395890 CLSTN1 3726772 CROP 368415 CLTA 3.011317 CROT 284253O CLTB 3302572 CRTAC1 3729172 CLTC 616166 CRTAP 29.065 CLU 4698.65 CRY1 3775808 CLUL1 391.149 CRYAB 29.45882 CMAH 2 6.85776 CRYBG3 34O7926 CMAS 24.18451 CRYZ 2668021 CMM6 392,982 CRYZL.1 2817464 CMYA5 34,57614 CS

3793.760 CNDP2 CSDA 2382419 CNH4 252 CSDAP1 397.1219 CNKSR2 4O6783 CSF3R 2980516 CNKSR3 3126504 CSGALNACT1 38.21263 CNN1 3243908 CSGALNACT2 Figure 6 continued

Patent Application Publication Oct. 27, 2016 Sheet 30 of 111 US 2016/0312305 A1

TCID GENEna2g TCD GENE na29 353995 DLEU2 31 1865 TDENND3

3362263 DENND5A 34.35490 DENR

3943101 DEPDC5 3565663 3151401 DERL1 3742756 DERL2 2528476 DES T 2333794 DMAP1 4004044 DMD 3859761DMKN 3520934 DCT 3O392.47 2336.809 3487095 DGKH 3074912 DGK 3092325 DCTN6 2326496 DHDDS 2825514 DMXL 2726828 DCUN1D4 3667811 DHODH 2992243 DNAH11

2849056 DNAH5 2397025 DHRS3

3153633 DDEFT1 2593013 DNAH7 23219 DD2

2969350 Doo

2364231 DDR2 2343289

3250055 DDX21

2336891 DO1 3292413 DNAJC12 3573870 DO2

3214227 DIRAS2 2806256 DNAJC21 24.17362 DIRAS3

2385343 DISC1 3184940. DNAJC25 GNGO ,

2340350 DNAJC6

2382360 DEGS1 31251.16 DLC1 2944068 DEK 2678298 Figure 6 continued Patent Application Publication Oct. 27, 2016 Sheet 31 of 111 US 2016/0312305 A1

TCID GENE na29 TCID GENE na29 TCD. GENE na29 260277O DNER 2360633 EFNA4 2600155 DNPEP 2869880 EFNA5

32595.03 DNT 3557408 EFS DNTTP2

3159330 DOCK8 2830861 EGR 3291601 EGR2 3929821 DONSON 392975 DONSON 2391425 DVL1

3013565 DYNC11 4037595 DYNC12 3325052 EF2AK2 2515276 DYNC12 2563654 EIF2AK3

298.1874 DYNLT1 3544387 EIF2B2 4004 89 DYNLT3 2409904 EIF2B3 2376894 DYRK3 m 2330002 EIF2C T 4.88252 DYSF 39.03288 2443.120 386 DYTN 33O9215 3065546 DPY19L2 3625391 DYX1C1 584,712 2483544 352t 372 3.945056 2635.263 655688 448 E2F2 40O373 2 612371 EAF1 44 311 1695 EBAG9 553607 EIF5 883878 EBF1 37.88270 ELAC1 2424524 DPYD 1284.11 EBF2 48689 EAVL1 3 873923 EBF4 ELF4 3984,702 DRP2 7098 ELK3 ELMO1 241.3032 ECHOC2 ELMO2 ELOVL.1 ELOV2 ELOVL4 3783529 DSG2 ELOVL6 ELP2 2893794 DSP 2608801 EDEM1 ELP3 2447824 EDEM3 ELTD1 EMCN EDN3 EM2 562435 EM4 34831.59 EML5

960903

2815139 DULARD O92O

396.2997 554.018 NAH 3592214 DUOX2 3O87438 EFHA2 NAM 2685472665.472 3345427 3622239 DUOXA1 226709 Figure 6 continued Patent Application Publication Oct. 27, 2016 Sheet 32 of 111 US 2016/0312305 A1

TCD GENE na29 TCD GENE na29 2395490 ENO1 AHO1 AHD2A AHD2A 3795868 ENOSF1 2 AHD2B 2925953. ENPP1 24.9406494O64. FAHD2B 2984835 FAM103A1 2955673. ENPP5 3769969 FAM104A 3259253 ENTPD1 25.34664 327883 FAM107B 3230733 ENTPD2 3869097 FAM107B 35681.84 ESR2 3331926 FAM111A 3331903 FAM111B 3696226 ESRP2 2455933 ESRRG T 3029230 FAM115C

3 3355021 FAM118B

- 2997.907 EPDR1 2632225 EPHA3 4022925 FAM27A 3025.005 EXOC4 2643592 EPHB1 2655845 EPHB3 3028.858 EPHB6 3485883 EXOSC3 2346625 EPHX4 3225952 FAM129B 3772187 2456746 5908 1949 EPS8L1 2403335. EYA3 351698 EPST1 3078348 EZH2 3728588 EPX 2868.131 3720402 ERBB2 3265432 FAM16081 3417249 ERBB3 2597.552 ERBB4 3865378 ERCC1 2423907 F3 3104323 FAM164A 3836217 ERCC2 2443370 F5 3288707 ERCC6 4027639 F8 4012142 ERCC6L 2334740

2858752 ERCC8 3.931765 ERG 2519294 FAM171B 357.0049 ERH 314238 FABP4 O65 683845 365.1509 ERLIN1 3564790 ERO1 3333226 FADS2 3532353 FAM177A1 246.2329 ERO1B Figure 6 continued

Patent Application Publication Oct. 27, 2016 Sheet 35 of 111 US 2016/0312305 A1

TCID TCID ENE na29 2437.205 GBAP NG12 26841 87 GBE1 GBF1 GBGT1 GGTC3 GNG7 2421843 GBP1 303556 GMAP2 GN1 242.1883 3031533 GMAP4 GNL3L 24.21925 3031573 GIMAP5 GNL3LP 2421883 3079103 GIMAP6 GNMT 2421843 GBP3 3031517 GIMAP7 GNPAT 242.1925 O31466 GMAP8 GNPDA. 242.1883 8808 2 7 GNPNAT1 242.1995 GBP4. 703112 GNPTAB 24.21925 GBP4. 471005 GT2 2422035 656032 GOLGA1 2345.816 GBP6 3656032 GIYD2 GOLGA4 GBP7 GOLGA8A GCA GOGA8A 394.5014 GCAT GOLGA8B 26.36062 GCET2 3504213 GJB6 3617574 GOLGA8B 2688805 GCET2 3212848 GOLM1

GOLM1 3585524 GCH1 2668205 GLB1 GOLSYN 8468 GCK 2451931 2957560 GCM1 3197955 GLDC 2437645 5441 GCOM1 2971378 701.459 GCSH 2669888 3174510 40498.35 GOT1L1 31.03607 GDAP1 3422855 GLIPR1 3707335 GP1BA 2430370 2711627 3306984

3197014 GLIS3 382.9174 GPATCH1 3824993 GDF15 2749,191 GLRB 2402861 GPATCH3 3996404 GDI1 3271018 GLRX3 375918.6 GPATCH8 3275132 GDI2 2520291 GLS 3729014 GDPD1 . 3437.500 GLT1D1 4022.447 GPC3 3382319 GDPD5 3824471 GLT2501 5808 GPD1. 3144934 GEM 2676319 GLTBO1 511432 2477980 GEMIN6 GLT8D2 7038 2649640 GFM 3451246 GLT8D3 2794584 GPM6A 3978169 GLTSCR2 2474681 GPN1 447066 GLUL 3191273 GPR107 3308241 GFRA 2487.478 GMCL1 2955932 GPR110 3127156 GFRA2 2487.478 GMCL1 L, 999 GPR110 3685183 GGA2 3914021 7 8 3861948 GMFG ;1 334 GPR124 2898597 76327847 GPR125 37961 GGNBP2 2 528620 GMPPA 1404 210737 343806122;3 GPR133 O10439 GNA1 2386747 GPR137B 7792O7 GNAL 2505779 GPR148 661940 GNAO1 2587790 210808 GNAC) 2851.835 GPR160 391840 2442911 GPR161 3402874 3978169 GPR173 84 94 O 3982612 GPR174 312Figure 6 continued Patent Application Publication Oct. 27, 2016 Sheet 36 of 111 US 2016/0312305 A1

TCD GENEna29 CD GENE na29 2350922 GSTM2 2351004 GSTM2 HBP1 HBS1 L. 2350952 GSTM2 HCFC1 HCFC1R1 2350922 GSTM4 HCFC2 2350.981 2756309 hCG 1771830 2350922 TGSTM5 3621728 hocG 17897.10 3994984 GPR50 2351004 GSTM5 hCG 2024410 3262.509 GSTO1 387.1459 hog 2039146 2855963 HCN1 2553262 GPR75 2727.535 IGSX2 2907173 HCRP1 2328387 CRTR1 2606026 DAC4 4.012204 HDAC8 2991.395 HDAC9 444 HDHD1A 2462456 2386867 HEATR1 2777639 GPRIN3 3659888 HEATR3 2902013 GTF2H4 3559690 HEATRSA 30.08376 GTF2 3765059 HEATR6 2835715 GPx3 3008376 GTF2IP1 3056656 GTF2RD2 3559570 HECTD1 3257,750 HECTO2 409970 HECTD3 334 2827057 GRAMD3 2593352 GTF3C3 909 342O497 HELB 3258910 HELLS 3770743 GRB2 2776026 HELO 2469825 GREB1 3768015. HELZ 3217.077 2325358 GRHL3 2787958 8650 2749222 GRA2 3614901 ERC2 3989448 GRA3 3585749 ERC2 4050485 GRIN1 36i.3936149012E.98 ERC2P2 370422 GRN2C 3558375. GZMB 3585.749 ERC2P2 32.1815 GRIN3A 3558375 GZMH 361 4901 ERC2P3 359544 GRINLA 2809793 GZMK ERC2P3 3071063 GRM8 ERC3 3790529 GRP ERC4 2835006 IGRPEL2 2946714 H2BFS ERC6 2772614 GRSF1 3770944 ERPUD1 3755903 GSOMB 2605735. HES6 34451.56 GSG 3632152 HEXA 3741585 GSG2

2691014 GSK3B 3757288 THAP1 3187686 GSN 2832052 HARS 3723348 HEXIM1 3903670 GSS 2832052 HARS2 2422612 IHFM1 2350922 GSTM1 2745899 HHIP 2350952 GSTM1 Figure 6 continued Patent Application Publication Oct. 27, 2016 Sheet 37 of 111 US 2016/0312305 A1

TCID TCD ENE na29 TCID GENE na29 2635184 HHLA2 2401275 NRNPR 3938113 HC2 3539070 F1A 2655325 HTR3C

3836705 2655325 HTR3D 2739160 HOXA13 3057370 HOXA4 3049840 HUS1 23527.58 HOXB8 4009315 HUWE 3075778 HOXD1 3325907 HOXD9 3697434 HYDIN 637 2400322 HP1 BP3 3952703 3394123 HYOU1 2822407 2794408 HPGD 253982 AH 3621276 HISPPD2A 3830065 HPN 2380991 ARS2 2946194 HIST1H1A 2735129 BSP 2946714 HIST1H2BK 27.00244 HPS3 2948215 HIST1H3B 264726 THPS3 899233 HIST1H3E 3358090 HRAS 3820443 2899146 HIST1H4C

2 947081 HIST1H4 28951.59 HIVEP1 2656650 HRG 2977265 HIVEP2 3145980 HRSP12 240-1493 D3 3250278 3300350 IDE . 2.94.8926 HLA-B 2597010 IDH1 2948887 HLA-B 3671448 HSBP1 3603199 DH3A 294.8926 HLA-C 3273601 : D1 2948887 HLA-C 3216,195 HSD17B3 3095223 DO 2950263 HLA-DMB 3417703 HSD17B6 3095257 DO2 295.0329 HLA-DPA1 2903488 HSD17B8 4025339 IDS 2903401 HLA-DPB1 312O358 295.0125 HLA-DQB2 29238.19 HSF2 31.89 HLA-DRA 4O2S485 HSFX1 2362394 F16 901820 40254.85 HSFX2 2343511 F44 3727583 HLF 3400034 HSN2 3881282 HM13 3580179 HSP90AA1 3 580179 HSP90AA4P 3602873 HMG20A 2908474 HSP90AB1 474 HSP90AB3P 3201242 IFNA10 3431483 HMGA1 HSP90B1 3204.242 IFNA16 HSP90B3P 3874.402 HSPA128 3201242 FNA21 3994.915 HMGB3 ... 3925.439 HSPA13 3201242 IFNA4 2329386 HMGB4 2707 HSPA1A 3201242 IFNA7 2707 HSPA1B 9450 HSPA1 L. 3201359 FNE 2448198 FRG15 28.38656 HMMR 742935 HSPA4 284.802 HMP19 HSPA5 413519 692.136 HSPBAP1 3610804 IGF1R 2352609 HNRNPA3 593733 2708922 TGF2BP2 4. OO 79 3 3041409 GF2BP3 2775463 HNRNPD 508330 2934308 IGF2R 2730 194 HTN3 4037595 HNRNPM HTR1D Figure 6 continued Patent Application Publication Oct. 27, 2016 Sheet 38 of 111 US 2016/0312305 A1

TCTD GENE na29 D TCID GENE na29 596.162 NO80D 255627 ITGA6 2 52011.3 345710 ITGA7 495446 261788 ITGA9 787459 3741585 ITGAE 267382 2519229 TGAV 942766 3852832 TGB1 2563785 IGKG 3284.188 TGB1 NPPL 2539765 TGB1BP1 502424 3724.545 TGB3 2416218 ITGB3BP 8405 NTS10 2692816 TGB5 738314 NTS12 2583465 ITGB6 383.081 NTS4 2991860 TGB8 383O81 NTS41 3499132 ITGB1 383.081 NTS4L2 3276337 TH5 3514,488 NTS6 751 TIH5L. 2742829 NTU TK 2597867 KZF2 0.13549 TM2A PCEF 3874.249 TPA PMK TPR1 811812 PO11 152 TPR2 PozO7 37.82 TPR3

.364 18779 TSN1 328767 VD 3472274. VNS1ABP 664 YD 3599059 JAK2 2649824 880361 UAKMP2 298 IQGAP2 i392i9 5 .i JAM2 366028 248986 MJD1C 2497.028 L1RL2 IRAK2 291682 MD1 C 3412296 MY 2798384 IRF2 i7 PH3 2453881 i1 K 2601995 IRS1

877C 3525234;222: RS2 150 4017694 8492 2846522 IRX2 39.98786 L1 2639734 KALRN 3850676 KANK2 36997.57 KARS 2978957 KATNA 3507962 KATNAL1 399.6971 3787187 KATNA2 2514413 KBTBD10 3401 119 33895.66 KBTBD3 3142485 MPA KBTBDB KBTBO7 2628260 KBTBD8 3071700 MPDH1 2427,619 KCNA3 2673873 MPDH2 64.8991 KCNAB' 3262129 NA 3103062 KCNB2 - 3554315 INF2 3462567 KCNC2 2536,757 ING5 2;3.3021009 KCND2 Figure 6 continued

Patent Application Publication Oct. 27, 2016 Sheet 40 of 111 US 2016/0312305 A1

TCTD GENE na29 TCID GENE na29 TCD GENE na29 944882 LGALS1 2839334 L1TD 3833183 LGALS13 396074 LGALS2 35367O6 LGALS3 3861557 LGALS4 24.62456 GAS8 386867 LGALS8

258713 G1 3127352 LG3

96.68 G4 357.7078 LGMN

367.096 GR4 44 GR5

2215 37.5144 GR6 2 C2 867573 HB 4019849 IAMP2 2552368 HCGR 2707876 LAMP3 2863885 HFPL2

2342475 285.4092 37.1840

3435362 KNTC1 4041113 KPNA2 2514122 ASS6 2703217 KPNA4 3724782 KPNB1 3030585 KPNB1 3348568 344.7863 KRAS 3422855 KRR1

3696.035 3415320 KRT 3653619

2762500 3455516 KRT8 3512874 34551.34 KRT80 2886595 2577856 3304215 LDB1 DB2 DHB

OLRAD2

23.6679.8 2340433 EPR 2340433 EPROT

Figure 6 continued Patent Application Publication Oct. 27, 2016 Sheet 41 of 111 US 2016/0312305 A1

TCD GENE na29 GENE na29 TCD GENE na29 LOC100128068LOC1001280.68 3987029 LOC10O 130886 3735847 LOC100.133227 3913018 LOC1001281.84LOC10012818.4 39461466146 LOC100-130899LOC100.130899 3930781 LOC1001.33286 3777470 LOC10028219LOC1001282.19 25403172 540317 LOC10030910LOC100 130910

3302056 OC10012832O 3275922 LOC100.130920LOC100 130920 3872604 OC100128398 2861952.2861952 LOC10030998LOC100.130998 38.17733 OC100128439 2602901 LOC100131015 3836.614 OC100128529 2533670 LOC100131101 2933175 OC100128551 3110272 LOC100131102 2606026 2565935 LOC100.133923 3848243 3890870 3020222

33961O7 765689 759587

2601.414 2900269

404,122 869880 604998 2691014 3696317 362303 LOC100129397 2779638 LOC100131829 3279108 LOC10O 1922O4. 2622026 LOC100131840 3260.001 LOC10027O71O 3050388 LOC100129.427 40271.764. 0271 76 LOC100131857OC100131857 3683050 LOC100271836

3513549 LOC10031993

3583541 LOC10032025

3392332 LOC100.32764

3542.45 LOC100130542.

2342220 LOC1001.33219 Figure 6 continued Patent Application Publication Oct. 27, 2016 Sheet 42 of 111 US 2016/0312305 A1

TCD GENEna29 9066O7 OC221442 937.967 OC26080 3684.782 LOC653390 953.456 OC26080 3029230 523499 OC283480 3641597 OC441734

7095 OC2835.08 542847 OC283567 LOC283.683 3201345 LOC554202.

368.3050 LOC641298

335812. LOC692247 2951567 LOC285847 2506335 LOC642669 68 LOC285972 139882 LOC2861.90 O300 OC339047 958 LOC3394.83 3583541 LOC727832 34 LOC340508 LOC 2506335 LOC644525 LOC388 3982423 OC644732 729 LOC LOC388931 LOC389137

OC389765 2340350 LOC645.195 1651 LOC389791 35835.41 LOC645202 32 O4.2 5 6 7i LOC39.0748 2539869 LOC392510 3283613 LOC645984 LOC4006BO 1 LOC400759 3203311 LOC646808 LOC400927 3826803 LOC646864 2487995 LOC728731 LOC400986 36.21276 LOC647471 275860258602 LOC72873.LOC728731 LOC401 O1O 3868330 LOC647678 32234253425 | LOC728779 4026 OC401218 2525533 LOC648149. 3754041375.4041 LOC728824 994 OC4O1317 060 OC401387

85 OC4O2509 .

OC402778 9911 770 OC440093 35.83541 OC440243 3614901 OC440248 3692701 LOC652708 248 4002011 258 3841777 OC652779 258 2500275 LOC72932 3583.2;652.077 354 354 724698 C440434 117 C440434 563785 C440871 375.4096 31 73508 897

E 2727226 L OC441016 2343823 LOC729828 Figure 6 continued Patent Application Publication Oct. 27, 2016 Sheet 43 of 111 US 2016/0312305 A1

GENE na29 GENE na29 LOC729882 2672190 LOC729991 3402984 LOC729991 3158812 31192.13 LY6K MEF2B 2704763 2583254 LY75 LOC730O31 3665.458 LOC730092 3767169 LOC730092 37671 69 LOC7301 10 3767169 LOC731528 767-169 LOC731788 3717452 LOC731985 1 7 5 2 LOC732428 425173 4031834 OC732.447 4177377C 4.D LRRC40 23.80785 LOC81691 712835

248986 LOC84 60O212

LOC90826 370269 954764 LOC91316 671607 938817 LOC9661O 2365086 7356 LONP1 3358090 LRRC56 9306 LONP2 R 342.1511 LYZ 3690 470 ONP2 3315907 567167 LONRF2 3988638 ONRF3 3106559 2331213 MACF1 234.1387 RRC7 2576281 MAD2L1 2811812 RRC70 2396781 MAD2L2 3190778 RRC8A 2714672 MAEA 345880 RRC8B 3905875 - MAFB 2345929 LRRCBC 3451814 3661718 LPCAT2 f 3 RC9 270867 1 05 RRCC1 3058209 2343823 LPHN2 534 RRFIP1 : 26.69184 RRFIP2 3745525 342470523T RRIO1 195 241.8339 RRIO3 2608309 RRN1 7 385515 MALAT1 3019158 RRN3 790259 MALT1 RTOMT 3174121 MAM DC2 6900 SAMP 2786732 L3 SDP5 3994.710 MAMLO1 2971801 MAN1A1 23.53881 2326049 MAN1 C1 3317O71 LSP1 2823551 MAN2A LSR 3608466 MAN2A2

3529877 LTB4R 3633347 MAN2C1 3529877 TB4R2 2779897 |E. 2476510 LTBP1 35.71944 LTBP2 291.7767 MANEA 2578790 LRP1B 2672140 LTF 586038 LRP2 3674960 LUC7L 796847 LRP2BP 34652 48 LUM 829242 RP3 3324.162 LUZP2 158812 RRC14 2824.902 LVRN 2525533 MAP2 898.746 RRC16A 31 19339 LY6E Figure 6 continued Patent Application Publication Oct. 27, 2016 Sheet 44 of 111 US 2016/0312305 A1

TCID GENE na29 TCID TGENE na29 TCD GENE na29 35 62 MDN1 MGAT4C 3733065 MAP2K6 MGC12488 2574798 MGC16121 2403O27 MAP3K6 MED10 MGC16385 29.30592 MAP3K7IP2 MGC2889 966 MAP4 3765689. MED13 MGC295.08 549260 MAP4K3 4037595 MED13L. MGC40069 2496727 MAP4K4 34.73O83 MED13 MGC87042 2330289 MAP7D1 322B635 2974.188 MGRN1 3227846 MED27 MGST1 . MA3 3788097 MAPK4 3.112713 MCA2 3111561 MAPK6 3707 MICALCL 3855538 IMEF2B 93 2866225 MEF2C NA 2827299 MEGF10 262292 MAPKAPK3 3223551 MEGFg OX 2488178 MEIS1 361.8333 MEIS2 9 MITF 2547.332 MEMO1 MX1 2547.332 MEMO1 MK67 MK1 2396.415 MASP2 3783788 MEP1B MK2 2500.550 MERTK 30761788 MKRN1 3240012 MAST 32824633282.463 MKXT 2404122 MATN1 3434.525 MLEC 3311342 METL10 3568667 MAX METTL1 1A 3808600 MBD2 METTL3

METTL7B 3453592 MLL2 365,1955 METTL9 38O8096 MEX3C 3674504 MC1R 384 4024092 MCF2 3.748798 MFAP4 323823 MLLT10 3924518 MCM3AP

392.4518 MCM3APAS 2653932 MFN1 37356233.3 MFSD11 2 376548185 996 MFSD4 274664 MMAA MFSD6 2334350 MMACHC 714200 MFSD7 3763270 MMD 785.035 3388807 MMP O28011 MGAM 3388893 MMP3 890859 MGAT1 3329343 MDK 534.866 MGAT2 226883 MGAT2 3143660 MMP16 342.1300 IMDM2 5 66414 MGAT4A 3883236 MMP24 89.0239 MGAT4B 3753760 MMP28 Figure 6 continued Patent Application Publication Oct. 27, 2016 Sheet 45 of 111 US 2016/0312305 A1

CID GENE na29 TCD GENE na29 2735759 MMRN1 2817837 32.98924 MMRN2 90 2 6 3 2696784 SL2 2748163 MND 397.9659 2362333 MNDA 12557.1 SR1 247.0838 2674602 ST1 931970 320231.6 MOBK2B 2835662 MST150 622934 3992.408 MST159 593O14 26746O2 MSTP2 338O8O 26746O2 MSTP9 745351 36621O6 MT1A 444 63 MYH10 682O28 8392O6 745.429 3475295 MORN3 999 MTG 74535 6622O1.3 MT1H 745.429 4022833 MOSPD1 36336636632662236 MT1P 3745.429 662139 MT1JP 3745351 662130 M1L. 7504 MYH6 3480013, MPHOSPH8 3662150 MT1M 3557504 MYH7 3476012 MPHOSPH9 3662201 MT1P2 45.429 2333107 IMPL 3662150 TMTP3 3745.351 2594987 MPP4 77594 5 1 597389 32O6 MPP6 714200 32826O1 MPP7 651671 79.9167 2952,102 MTCH1 850071 3367673 2520429 33 7 3752709 12541 3O7633 3626826 2545653 MPV17 3431071 2370317 MR1 354OOO7 36246O7 2915571 MRAP2 3807595 2598496 MREG 3807965 IMRO 2443952 MYOC

MRPL14 3361116 MRPL17 3379708 MRPL21 3619479 MRP42P5 3764471 MTMR4 3218067 MRPLSO

O99 273872 NAAA 2808612 MRPS30 3344142 NAALAD2 3510925 MRPS31 3409330 MRPS35 2520225 NAB1 347809 NAB2

2898452. MRS2 3074912 NAG20 MS4A1 3997.825 MXRA5

3374934 3374934 MS4A6A 24.80992 MSH2 40.14759 Figure 6 continued Patent Application Publication Oct. 27, 2016 Sheet 46 of 111 US 2016/0312305 A1

GENE na29 TCD 880 NCRNA00085 2332013 NFYC 3656835 NCRNA00095 35291.56 2 762944 NCRNA00099 3985534 NGFRAP 3778823 NAPG 40282O7 NCRNA00105 2666566 NGLY1 3868400 NAPSA 390976 NCRNA00115 278OO60 NHEDC1 3879372 NCRNA00153 278.0099 NHEDC2 363O84 NCSTN 2363.128 NHLH1 3627363 NARG2 O37595 ND1 3265047 NHLRC2 380967 NARS NDC80 2674526 NCN1 2334404 NASP 495.076 246260 615556 NDNL2 555736 3323052 NAV2 NDST2 613338 254.1230 NBAS 825838 NDUFA13 613300 3485292 NBEA 8400 NDUFA4L2 3146012 NIPA 2 2506335 NBEA 965674 NDUFAF4 NIPA3 341497 NDUFC2 806799 NIPBL 2621 22 NBEAL 2 2363525 NDUFS2 956909 NIPSNAP1 331 178 NDUFS5 182957 NIPSNAP3A 7782O7 NDUFV2 3182957 NIPSNAP3B 392.2921 NDUFV3 218528 NIPSNAP3B 2623859 NSCH 363389 NT 106479 NECAB1 924081

789947 NEDD4. 3 128271 NEFL NKTR 3090436 NEFM 83 NLGN3 234. 1. 7389 NLK 2432851 NBPF15 85i 181 NEI2 NLN 2357217 NBPF15 2666884 444 NLRC5 243285 NBPF18 31908 NLRP14 3636985 2432851 NBPF20 4 NELL2 2877231 2 6 7 31 36 2432851 NBPF8 949471 NMNAT2 NMNAT3 2432851 NBPF9 717052 NF1 NM NFAT5 NMT2 795184 NFATC1 NMU NFATC3 NMUR2

3915936 NFE2 NOC2L 588827 NFE2L2 NOC4L 3724591 NFE2L3 3 3181302 NCBP1 3590 NFE23 NOL4 2338719 NFA NOL7 3.1992O7 NFB NOL8 NFL3 NOLC1 2634091 NFKBIZ

3903525 NCOA6 2558118 NFU NOP14.

Figure 6 continued

Patent Application Publication Oct. 27, 2016 Sheet 48 of 111 US 2016/0312305 A1

TCID GENE na29 TCD GENE na29 3294.159 P4HA 2832467 PCDHB18 2832325 PCDHB19F

2831209 IPAP2 2659577 PAK2 2832315 PCDHB4 2832325 PCDHB5 3381 150 PDE2A 2832355 PCDHB6 2340529 PDE43 2822215 PAM 2832325 PCDHB9 2858134 PDE4D 34,57696 PAN2 2832533 PCDHGA1 431886 PDE4DP 3483159 PAN3 2832533 PCDHGA10 596 3874533 PANK2 2832533 PCDHGA11 2714132 PDE6B 2832533 PCDHGA12 3 1384.64 POE7A 3543539 PAPLN 2832533 PCDHGA2 3606034 PDE8A 2832533 PCDHGA3 28.16681 PDE8B 2832533 PCDHGA4 3922793 PDE9A 3256590 PAPSS2 2832533 PCDHGA5 79.1197 2832533 PCDHGA6 3 2832533. PCDHGA7 727226 PDGFRA 2832533. PCDHGA8 7703 2832533 PCDHGA9 0833 PDHA 2832533 PCDHGB 49 PDHX 2832533 PCDHGB2 92.25 PDIA5 2832533 PCDHGB3 9529 PDA8 2832533 PCDHGB4 0317 PDA6 2832533 PCDHGB5 2082 2811145 PART1 2832533. PCDHGB6 PDLM1 2832533 PCDHG87 279695 PDLM3 2832533. PCDHGB8P 2828441 2832533. PCDHGC3 2736322 POLIM5 3532793 PAX9 2832533 PCDHGC4 2768588 2832533 PCDHGC5 3484768 PDS5B 3342525 PCF11 3650300 PDXDC2 PDXK PDZD11 PDZK1 P1

PDZRN4 PEBP4 PECAM1. 293O863 PCMT1 PEC PECR 303255 2832423 IPCDHB10 387,2053 5563O2 ELI1

537164 EL2 2832392 PCDHB13 809128 EELO 2832325 PCDHB14 3877892 IPCSK2 2976360 PCSK6 3061.191 PEX 1

3753690 24460 015 174 79 Figure 6 continued Patent Application Publication Oct. 27, 2016 Sheet 49 of 111 US 2016/0312305 A1

TCl D TCID GENEna29 TCIO GENE na29

2465551 2905296 P16 3133233 PLAT 2707045 PEX5 3252036 PLAU 3709540 3294.959 2440612 2475042

4009811 PFKFB1 3875842 PLCB1 2377094 PFKFB2 3334372372 PLCB3PCB3 3233605 PFKFB3 343344 PFKM 7OO585 3493448 PBF1 2780 PGA3 332780 2602653 PID1

332780 PGA5 593.407 PGAP1 PGBD2 3833443 3288707 GBD3 2714025 PIGG

3 108226. PGCP 287.1685 PGGT1B 23397.86 PGM1 3811086 PIGN PGM21 339124 PHD2 173 1735.08 PGM5P2 2395890 3824963 PGPEP1 740 PGRMC1 2813060 . PIK3R 2410470 PIK3R3 2995.189 PLEKHA9 38.91530 PHACTR3 2505957 PLEKHB2 3981 PHC1 3015442 PILRB 3107828 PLEKHF2 3403981 PHC1B 3832992 PLEKHG2 2400212 PNK 27.98475 PLEKHG4B 2 704894 PHC3 3569339 PLEKHH1 397145 PHEX 2479433 PLEKHH2 PHF1 37'59849 PLEKHM1 PPSL 3759849 PLEKHMP 9481 PHF11 3957938 PSD 3598.165 PLEKHO2 3751184 PHF12 3732230 PTPNC1 2492659 PLG 7330E.8 990 0.43 PHF14 3437801 2492659 PGA 3 30497OO 2492659 PGLB1 3697933 PKD1.3 492659 PLGB2 743315 PHF17 2735221 PKD2 6 546 PLN 116535 PHF2O1 527.196 PLK1 944 PHF3 2858023 PLK2 991 3631964 PKM2 2923270 PLN O09 2699564 PLOD2 O12299 PHKA1 3977O67 PLP2 51g 56 69 3354535 PKNOX2 2645906 PLS1 3359461 PHLDA2 345.0234 PKP2 3987.996 PLS3 635906 PHLDB2 251820 PKP4 2699.623 PLSCR4 791482 PHLPP 39.07524 PLTP 428699 PHTF1 3854417 PLWAP 278198 PHYH

190796 PHYHD1 127385 PHYHIP PLA2R1 .

247977 PHYHIPL 3426502 PLXNC1 3290649 PHYHIPL Figure 6 continued Patent Application Publication Oct. 27, 2016 Sheet 50 of 111 US 2016/0312305 A1

TCD GENE na29 TCD GENE na29 TCID GENE na29 36.98081 PMFBP1 3192033 PPAPOC3 444578 PRB3 396.2000 PMM 2763550 PPARGC1A 44578 PRB4 3647504 PMM2 773358 PPBP 39031 PRC1 2773407 PPB PL2 3384270 PRCP 2919669 PRDM1 2934,191 PNLDC1 3483821 PPFA2 E. PRDM15 34O9211 PPFBP1 2316953 PRDM16 3128731 PNMA2 3319137 PPFBP2 2321238 PRDM2 2357217 PPAL4A 34.70037 PRDM4 2357217 PPAL4B 3851776 2357217 PPAL4C 3483885 PRDX2 2357217 PPA 4G 2367.743 PRDX6 PPB 2474.265 PREB 2365496 POGK 2873105 PPC PREPL 3938244 PPL2 3102098 PPL4 345.375 PRCKLE1 3678462 PPL 400 7865 PRCKLE3 238962 PPM1F 2337716 PRKAA2 568 PPM1M PRKAB1 3107342 PPM2C 2433209 PRKAB2 PPP1CB 3852.529 PRKACA PPP1CC 344,393 PRKACB PPP1R10 PRKAG1 71 PPP1R12A 3732885 PRKAR1A PPP1R13B 3018375 PRKAR2B PPP1R13L PRKCB PPP1R14C 2624291 PRKCD PPP1R15A 24801.68 PRKCE PP1R16B 3538.893 PRKCH 1 PP1R1A 2651916 PRKC

2O PP1R1B 3275922 PRKCO - PP1R1C 686 PPP1R3A 2880.051 EEPPP2R2B 2759205 PPP2R2C

3271687 PPP2R2D

PPP2R3A 2334602 IPOMGNT1 3532353 PPP2R3C 3057755 POMZP3 355272g PPP2R5C 3061942 PON1 567984 PPP2R5E 3061997 PON2 779638 PPP3CA 3061964 PON3 294499 PPP3CB 3g24783 PRMT2 3798291 PPP4R1 PRMT3 3836760 PPP5C 2349848 PRMT6 3009229 POR 34.71300 PPTC7 PRO2012 3814701 POLC1 8 PROCR

2321058 PRAMEF1 PROKR1 2321058 PRAMEF13 2321058 PRAMEF14 2685304 ROS1 2414366 232,058 PRAMEF2 2379665 PROX1

3444578 2358171 PRPF3 Figure 6 continued Patent Application Publication Oct. 27, 2016 Sheet 51 of 111 US 2016/0312305 A1

TCTD GENE na29 GENE na29 96047 sTPTE22 35342.01 PRPF39 sPTE22 3329983 PTPRJ 322.1543 PRPF4 912861 PSMA7 358906 PSMB4 PSMB9 3413852. PRPH 372209 PSMC3 398854 PRPS1. 721886 PSMC3IP 3833291 PSMC4 PRPSAP1 2404254 3838624 PRR2 2 542816 PUM2 2512701 PSMD14 PURA 299498 PRR5 2655650 PSMD2 315739 PUSL1 2984543 PVRG 394.8259 PRR5 PVRL1 3722152 PSME3 6884 99 PVRL2 387.338g PSMF1 641

2386798 PRRX1 3035408 PSMG3 134922 PXDNL 3028766 PRSS1 2626167 3880767 PYGB 3215851 PTCH1 EEPVR 3028766 PRSS2 356,4210 PYGL. 3343452. PRSS23 37.27787 625440 PYGO TI 3028766 PRSS3 37.27787 PTENP1 HN1

3236786 PTER 3302740 PRUNE 752 PTGDR PZP PRUNE2 3537.17 PTGFRN PZP PRUNE2 220673 PTGR1 27.62334 OOPR PRY 448382 PTGS2 2477438 4038437 . PRY2 1563O7 PTK2 QSER1 907671 PTK7 2369950 175971 PSAT1 PTMA 3638204 CTRT1 402736 PTMS 382O727 QTRT 1261.91 4857 1 PSD4 839006 PTOV1 82 911903 PTP4A1 313f 741 24O4819 PTP4A2 2875 761 PSG1 118818 PTP4A3 872 63929 PSG11 18O142 PTPDC1 616 3279982 PTPLA f 70 3761 1646O1 PTPLAD2 9 58670 761 241.1 PTPLB 2361257 329886 PTPMT1 625271 863761 888721 PTPN1 788976 863929 959 PTPN12 863761 34629 PTPN13 929699 863929 PSG6 55418 PTPN14 751002 863761 2505529 PTPN18 2B10805 9 262333 PTPN23

386376 PSG8 - i2 i6 3863761 PSG9 3270270. PTPRE 3686750 2333318 PTPRF 3188299 RABGAP1G AP1 Figure 6 continued Patent Application Publication Oct. 27, 2016 Sheet 52 of 111 US 2016/0312305 A1

TCD GENE na29 2395245 RERE 29890.50 3944210 RASD2

3454223 RACGAP1 281794 RASGRF2

3454223 RACGAP1P 3867346 RASP1 3482845 2867788 RFESD 328676 RASSF4 3210457 RFK

3590086 RAD51

3439836 RAD52 298.8459

363960 RGMA 28276 RGMB 2815488 RGNEF 2499158 RGPD1 2663244 RAF1 2499158 RGPD2 2499158 RGPD3

3976519 RBM3 2499158 RGPD5 3033397 RBM33 2622469 RBM5 237278 RGS1 3642707 RGS11

237282 IRGS13 3417583 RBMS2 244.7148 RGS16 3105271 2615060 RBMS3 2372719 RGS18 3438027 RAN 3914307 RGS19 2319550 RBP7 RGS2 T 3092415 RBPMS RGS5 3930235 RCAN 2447.192 RGS8 2325479 RCAN3 373.543 RGS9 2683244 253.0330 RHBDD1 2400655 rapt GAP 351.3549 RCBTB2 736853 1GOS1 7659 2A 3336486 RCE1 2674242 RHOA 3325503 RCN 2749699 2724671 RHOH 452690 2515783 238440 RHOU 3416921 RDH5 401.9700 RHOXF1 595560 3753896 RDM 3390542 RDX 3430331 RIC8B 614369 3397.877 RCS 3456081 . 3248999 REEP3 25.0485 RF 3333899 RRES3 287.1176 REEP5 2839671 2819044 A1 26455.79 2765865 3110395 RIMS2 3065154 SA4 337819 RN1 3065154 RASA4B 3970214 REPS2 3781654 RIOK3 Figure 6 continued

Patent Application Publication Oct. 27, 2016 Sheet 54 of 111 US 2016/0312305 A1

T TCID GENE na29 TCD GENE na29 RTN4P1 SEC22B RTP4 3561952 SEC23A RUFY3 RUNX1 RUNX1 T1 RUNX2 3235414 SEC6A2 RUNX3 3928.040 RWDD2B 3972093 SCARNA23 49484 p1

3280586 SCD 2435005 SELENBP1 3O RYR1 RYR2 2224045676 S100A1 2601.230 SCG2 2435383 S100A10 2435410 S100A1 2649824 SCHIP1 SEMA3C 3059667 SEMA3D 3059393 SEMA3E 2436088 S100A2 236342 SEMA4A 2584957 3393622 SCN4B 2565592 SEMA4C 4051226 SEMA4D 2359684 2692199 SEMA5B

3363868 ISCP2 3278234 SEPHS1 3505319 SACS 2336585 SCP2 3150289 SAMD12 25699.08 3252534. SAMD8 3962839 SCUBE T 3764527 SEPT4 336219. SCUBE2 3735847 SEPT9. 2904485 SCUBE3

3337618 SAPS3 2780734 SCYE1 3428131 SCYL2 SERF1B SAR1B SERGEF .

2773907 SDAD1 SERHL 34572.01 SARNP SERHL

SERH2

SERHL2

SERENC3 3476130 SBNO SERINC5 3844978 SBNO2 3577612 SERPINA 3577577 SERPINA10 3577612 2592532 SDPR 35497S7 3549740 SERPINA3 3549740 262.1333 SCAP 2938972 SERPENB1 3791996 SERPNB8 Figure 6 continued Patent Application Publication Oct. 27, 2016 Sheet 55 of 111 US 2016/0312305 A1

TCTD GENE na29 2601.414 SERPINE2

2651165 SERPIN1 3387259 SESN3 2374926 SHSA4 25.89929 SESTO1

2672532 SETD2 3579205 SED3 2978050 SHPRH 393O781 SETD4

26O9608 SETD5 34.89418 SETDB2

3228007 SETX 36872.77 SEZ62

3667281 SF3B3 94.2998 SF1 676518 SFMBT1 326774 SFN 39341 SK 132782 ISFRP1 966597 ISFRS17A 771800 SFRS2 2403740 SFRS4 2452754 f i. 3593575 2548970 SFRS7 2359885 2366156 ISFT2D2 3872945 SLC27A5 683 SFTA2 34.34308 2827645 SLC27A6 2562435 SFTPB . . . . . SIRT5 3042610 SKAP2 2988594 2651989 SKIL 24O904

SKV2

2974935

3450,899

4052021

3622436

2476116 2975014 SGK1 2349043 3.096 2725381 SLC30A9 310802 SGK3 27.01927 SLC33A1 3101765 SGK3 T 721959 SLC34A2 3289235 SGMS 3696035 SLC2A4 i O O 7 58 8 2738664 SGMS2 3617312 SLC2A6

2529421 SGPP2 3431892. SH2B3 T

3921442 SH3BGR 3290746 (SLC6A9 2960.955

2833924 SH3RF2 3542063 SLC39Ag

3380365 SHANK2 3158114 SHARPIN SHB Figure 6 continued Patent Application Publication Oct. 27, 2016 Sheet 56 of 111 US 2016/0312305 A1

TCTD GENEna29 . TCID GENE na29 3693673 3373845 SLC43A3 2745646 SMARCA5

2553911 SMEK2 3683050 SMG 2438.042 SMG5 2342624 SNORD45A 2860898 SMN 2814424 SMN1 2860898 SMN2 2814424 SMN2 3386814 ISNORD5 3696317 SMPD3 2575897 SMPD4

2730396 SMR3A 2730404 SMR3B 2730396 SMR3B 2444451 3666146 SLC7A6 397.1387 SMS 3686146 SLC7A6OS 3203382. SMU1 3557209 SLC7A8 30441 SMURF1 2619666 SNRK 2497252 SLC9A2 3695541 SC9A5 2464909 SMYD3 4052378 SNRNP35 4006841. SLC9A7 3740704 SMYD4 2699145 SLC9A9 3876245 SNAP25 3903052 SNTA

2696.11.3 SLCO2A1 2869096 SCO4C1 313958D SCO5A1 277714 SNCA 3725083 SNX11 286924 SCO6A1 3040073SNX18 3753568 SLFN11 296.3313 53500 SLFN11 3230332 SNHG7 3334.783 538 SFN12 3755198 SNP 37.535.38 SFN12 240763 SNP 98482 3753568 SLFN13 3386814 SNORA. SNX22 753500 SLFN13 3230332 SNORA17 3718555 SLFN5 2826343 SNX24 r 302187 SLT1 330925 SNORA19 2754582

SLT1 3398.40 SNORA23 383O864 720 SLT2 338684 SNORA25 2359036 NX2 7 5 SLRK4 2 37 NX7 3495968f53 SLTRK5 2369,557 SOAT1 SLITRK6 338684 SNORA32 3772279 SOCS3 SLMAP 16348472 3 SMO1 31 SORBS1 SLMO2 2558150 SNORA36C 796995 SORBS2 SLP 2797.202 SORBS2 3592109 2233352948 SORL1 SNORA43 2549092 Figure 6 continued Patent Application Publication Oct. 27, 2016 Sheet 57 of 111 US 2016/0312305 A1

C D TCD GENE na29 TCD GENE na29 39.60302 OX10 3060300 3257031 STAMBPL1 2897899 OX4 STAR 3447348 OX5 RP14 STARD13STARO 13 3364306 RP68 2870828 STARD4 280305 256543 STARD7 SP140 5.8752O 258752O PAG17 S18 7424.15 PAG7 182 2882098 PARC 302795 TSSBP1 301.1838 SEAP1 32T2777113 PARCL1 8 2420467 PATA1 2413685 348.1543 PATA13 251 8428 SSFA2 238,0440 SPATA17 34.08831 2726910 SPATA18 2.940551 2607262 STK25 2709750 SST 31461.03 STK3 2391647 SSU72 3976559 SSX1 34.13950 ESPATS2 3976559 SSX4 3361811 7415 SSX4 2585933 SPC25 3591.281 SPCS2 OO7415 27.52560 SPCS3 3976559 SSX5 400745 362.1948 PG11 3976559 SSX7 2834,503 PINK5 4007415 SSX7 90732O PINLW1 GTF2AL 7335 PNLW1 2699,1457676 55 ST3 64 SPINT1 356175 ST4 3135046556484999 ST18 404766 SPOCD1 3635198 ST20 876897 SPOCK1 ST3GAL5 735027 2633256 ST3GAL6 5 SPP 3361971 2548274 STRN 34.72 SPP2A 2656837 ST6GAL.1 3531 63 STRN3 358914 SPRED1 556752 742224 SPRY1 519309 SPRY2 381906 STXBP2 SPSB1 2350339 STXBP3 190558 2929870 STXBP5 482.505 SPTBN1 573152 SPTLC2 3513293 876990 SPTLC3 114832 SQLE SQRDL 3015338 STAG31 3 305338 STAG32

388419 SRC 3015338 TSTAG33 3056705 STAG33

3237088 STAM 3656 Figure 6 continued

Patent Application Publication Oct. 27, 2016 Sheet 59 of 111 US 2016/0312305 A1

TCTD GENE na29 TCD GENE na29 3039.399 O465 925,590 3969 15 TLR8 435 166644 3745525 TM4SF4 961.317 TM6SF 725332 2550542. THADA TM7SF3 690850 3067644 3110608 TM7SF4 708817

881 TM9SF4 611779 3625391 E TMBM6 633691 TMEM45A 635578 TMC3 4004575 TMEM47 6854 650762 TMC7 TMEM48 3677356 HOC6 694931 TMCC1 TMEMSOB 6046 MCC2 409770 TMEM53 26.66147 THRB 3466206 TMCC3 235 TMEM55A 1497 THRSP 2442134 TMCO1 23477.32 TMEM56 351487.9 THSD1 3048778 TMED4 3825244 MEM59. 3514879 HSD1P 2423264 TMED5 3058,156 TMEM60 3600283 HSD4 287.1821 TMED7 3591281 TMEM62 A1 3182229 TMEFF1 3129948 TMEM66 629 AL1 592598 TMEFF2 3136O15 TMEM68 928668 AM1 3763390 TMEM100 2351632 TMEM77 2508 AM2 3722479 TMEM106A 2427720 TMEM77 ICAM O342 TMEM106B 3358262 TMEM80 E1 13278 TMEM106C 336126 TMEM80 782230 TIFA 2995 735598 TIGD2254. 3471769 TMEM116 3620515 TMO4 TMEM117 2 2374956 TMM17A f 3709153 28903 TIMM23 58 TMEM128 2450 383,3093 TMM50 806.8 TMEM132D 3976341 TIMP1 147 TMEM133 37.17870 3772661 TIMP2 397461 TMEM135 1812 3504 TIMP3 TMEM136 3594031 TIMP4 029016 TMEM139 012 TNF2 749380 TMEM144 649113 TPARP 3830530 TMEM147 272982. TMPRSS1E2 511 TPN 910364 TMEM14A 3393536 MPRSS13 . TIPRL 27O1294

562387

008 TAP1 766289

23342 3615579 TP1 173880 TJP2 381716 TJP3TT 3068476 3425134 TMTC3 TK2 751042 RAPE. 32 1579 TLE1 3031624 TMEM176A 322270

176209

3211579

O78321 750753 3597.125 Figure 6 continued Patent Application Publication Oct. 27, 2016 Sheet 60 of 111 US 2016/0312305 A1

TCD GENE na29 TCTD GENE ma29 3150455 TNFRSF11B 3645555 TNFRSF12A 3528172TRAG) 3648391 TNFRSF17 3441849 TNFRSF1A TRIP13 2956052 TNFRSF21 TRIP4 2705706 TNFSF10 369,5433 TRT1 3487299 TNFSF11 3553337 T6 3500787. TNFSF13B 25348.10 R 322228 TNFSF15 29.69810 TRAF3IP2 266.0648 2444239 TNFSF18 3715839 TRAF4 2 64595f RPC1 2705286 TNK 2378.662 F5 3903708 TRPC4AP 308527O TNKS 69 890 4018327 TRPC5 3373675 TNKS1BP1 541 8438 C6 3257850 TNKS2 34.32267 SE 3359267 Ebi TRPM5TRPt 234276 TNN3K 528172 17 362377 TRPM7 2342220 TNNI3K 2819120 E; 3149528 TRPS1 2450762 TNNT2 5 3 0.14411 TRRAP 3317117 TNNT3 139 rEf M 3028766 TRY6 3255402 TNPO 2957227 : 3228373 TSC1 3851651 TNPO2 P PC2 3512294 TSC22O1 3653898 TNRC6A RAPPC2P1 2647647 TSC22O2 . 3946192 TNRC6B 386.5223 RAPPC6A 39 TSC22D4 25991.53 TNS 155937 RAPPC9 3654 37 TSG101 3049522 - TNS3 3528172 RAV20 586 TSGA10 2949.622 TNXA 35281 72 RAV8-3 TSHR 2949822 TNXB 3528172 G 7 O56 TSHZ1 3762473 ITOB1 295.3570 TREM1 9419 TSHZ2 3907.111 TOMM34 T E 2 889624 TSHZ2 2906.720 RRA 858285 TSHZ3 2906720 TREM2P SO3618, TSN 2906720 TREM3 2334602 TSPAN1 3069955 TSPAN12

2954,022 TRERF1 2991 150 TSPAN13 2954.025 TRERF1 2842707 TSPAN17 3458783 SPAN31 TSPAN4 254420 TP533 TSPAN5 TSPAN6

TSPAN7 TSPAN8 TSPYL2 2915133 TPBG TSR1 TSSC1 3360622 TREM22 2654.306 TTC14 TTC17 TTC21B 2944.025 TPMT TTC23L 2466554 TPO TTC25 3361041 TPP1 TTC3 3499453 TPP2 TTC3 O 3643679 TPSD1 ; TTC30A 3005444 TPST1 2.845078 5 TTC30B 3955915 TPST2 311 1375 TTC35 Figure 6 continued Patent Application Publication Oct. 27, 2016 Sheet 61 of 111 US 2016/0312305 A1

TCID GENE na29 TCD GENE na29

2697.372 TXNDC6

24.02601 UBXN1 TXNDC6 3809324 TXNL1 342.9460 TXNRD1 77584 TYMS 250O803 TTL 379.5850 376155 TTLL6 95 TTLL7 TYRO3 3903942 TPA TYRO3 2754673 UFSP2 37.835.65 TT 3794 RO3P 3734236 TTYH2 590 3453837 TUBA1A 293215 TYSND1 2766456 UGDH 3453732 TUBA1A 2485257 UGP2 3453837 TUBA1B 453732 TUBA1B TYW1B 2853325 UGT3A2 3413787 TUBAB 3055608 1B 413787 TUBA1C U2AF2 2364155 UHMK1 575949 TUBA3C 631397 UACA 50618.5 TUBA3C 3641.89 UAP1 575949 TUBA3D 976062 UBA1 506,185 TUBA3D UBA2 2575949 TUBA3E 3451 96 2506185 TUBA3E 681 195 2528407 TUBA4A 2639874 UMPS 252B407 ITUBA4B 2642911 BA5 3167731 UNC13B 39365.15 TUBA8 277.1718 BA6

2674762 BA7

2O 753 BAP2 083 UBAP2 39888

w 327662 UPF2 380924O 3503224 UPF3A 3771.5434.58855582 UBE2O. 3065154 IUPLP 2451200 UBE2T 251712 UPP2 3725481 UBE2Z 2384705 URB2 2334279 UROD 3854311 USHBP1

352615 TUBGCP3 3936550 USP18 2353993

3749498 USP22

3685051 USP31 2668351. UBP1 USP32 USP32 3360553 UBQLNL 3220156 TXN 3620880 UBR4 290790 UBR2 SP40 SP41 SP44

966.298 Figure 6 continued

Patent Application Publication Oct. 27, 2016 Sheet 64 of 111 US 2016/0312305 A1

TCD GENE na29 TCD GENEna29 3014904ZNF655 3206317 ZNF658 2336539 ZYG A

261952 ZNF662

240269 ZNF683

3657318 ZNF720

4023006 ZNF7SD 3840 ZNF761 3840795 ZNF765

3826803 ZNF99 3668834 ZNRF1 2995.076 ZNRF2 3057755 ZP3 3057668 ZIP3 2462693 ZP4

3391769 Figure 6 continued Patent Application Publication Oct. 27, 2016 Sheet 65 of 111 US 2016/0312305 A1

CEL File Subtype Pathology Simplified Pathology 151276HUEX1A11CEL FA B 151279HUEX1A11CEL FA B 151326HUEX1A11CEL FA B 151329HUEX1A11CEL FA B 15134SHUEX1A1CEL FA B 151356HUEX1A1 I.CEL FA B 151359HUEX1A1 CEL FA B 1536HUEXA11CEL FA B 151364HUEX1A11CEL FA B 151793HUEX1A11CEL FA B 151794HUEX1A11CEL FA B 151795HUEX1A11CEL FA B 151797HUEX1A11CEL FA B 151798HUEX1A11CEL FA B 151799HUEXA11CEL FA B 151800HUEX1A11CEL FA B 151801HUEX1A11, CEL FA B 151802HUEX1A11CEL FA B 151803HUEXA11CEL, FA B 1S 1804HUEX1A11CEL FA B 51.80SHUEX1A1 CEL FA B 151806HUEXA11CEL FA B 151285HUEX1A11CEL LCT B 151291HUEX1A1 CEL LCT B 151294HUEX1A11CEL LCT B 151295HUEXAll-CEL LCT B 151305HUEX1A1 CEL LCT B 151309HUEX1A11CEL LCT B 151316HUEX1A11CEL LCT B 151336HUEX1A11CEL LCT B 151338HUEXA11CEL LCT B 151373HUEX1A1 CEL LCT B 151860HUEXA11CEL LCT B Figure 7

Patent Application Publication Oct. 27, 2016 Sheet 71 of 111 US 2016/0312305 A1

151866HUEX1A2CEL PTC M 151894HUEX1A11CEL PTC M

Figure 7 Continued Patent Application Publication Oct. 27, 2016 Sheet 72 of 111 US 2016/0312305 A1

CEL FileName Subtype Pathology Simplified Pathology FOO1200 B B FOO 2002 . B B FOO12003 B B FOO2004 B B FOO2005 FA B F0012006 FA B FOO12007 FA B FOO12008 FA B FOO12009 FA B F0012010 FA B FOO12011 FA B F0012012 FA B F0012013 FA B F00204 FA B F0012015 FA B F002O6 FA B F0012017 FC M FOO1201.8 FC M F0012019 FC M F0012020 FC M F0012021 FVPTC M FOO 2022 V FVPTC M F0012023 FVPTC M F0012024 HA B F0012025 HA B F002026 HA B F0012027 HC M FOO12028 MTC M FOO12029 NHP B F0012030 NHP B F0012031 NHP B F0012032 NHP B FOO12033 NHP B

Figure 8 Patent Application Publication Oct. 27, 2016 Sheet 73 of 111 US 2016/0312305 A1

FOO2034 NHP B FOO12035 NHP B FOO12036 NHP B FOO12037 NHP B FOO12038 NHP B F0012039 NHP B F0012040 NHP B FOO 2041 NHP B FOO12042 NHP B F002043 NHP B F0012044 NHP B FOO12045 NHP B F002046 NHP B FOO12047 NHP B FOO1204.8 NHP B F0012049 NHP B FOO12050 NHP B F001205 NHP B FOO12052 NHP B FOO12053 NHP B F0012054 PTC M FOO12055 PTC M F0012056 PTC M FOO12057 PTC M FOO12058 PTC M FOO12059 PTC M F002060 PTC M F0012061 PTC M F0012062 PTC M F0012063 PTC M F0012064 PTC M FOO12065 PTC M F0012066 PTC M F0012067 PTC M

Figure 8 Continued Patent Application Publication Oct. 27, 2016 Sheet 74 of 111 US 2016/0312305 A1

F002068 PTC M F002069 PTC M F002070 - PTC M F0012071 PTC M FOO12072 PTC M FOOl2O73 PTC M FOO12074 PTC M

Figure 8 Continued Patent Application Publication Oct. 27, 2016 Sheet 75 of 111 US 2016/0312305 A1

Rank Gene Symbol TCD Ref Sea SEMA3D 305.9667 NM 152754 2 MTG 3692999 NM_005950 3 MGC26647 3060450 BC028365 4 CLDN16 26S7808 NM_006580 S DPP4 2584.018 NM_001935 6 LPH 2708855 NM 139248 7 TM7SF4 3110608 NM 030788 8 RAG2 336993 NM_000536 9 SLC26A4 3018605 NM_000441 O STK32A 2834282 NM_001112724 11 CD36 301.0503 NM_001001548 12 PLA2R1 2583374 NM_007366 13 ELMO1 30461.97 NM_014800 14 TCD2526806 2526806 unknown 15 NELL2 3451814 NM_006159 6 CXCL9 2773947 NM_002416 7 CYSLTR2 3489138 NM_020377 18 LONRF2 2567167 NM_198461 19 TMSL8 4.016193 NM_021992 20 CXCL13 2732508 NM_006419 2 RGS13 2372812 NM_002927 22 PSD3 312691 NM_0153io 23 TNFRSF17 3648391 NM_001192 24 TSPAN8 3461981 NM_00466 25 CXCL11 2773972 NM_005409 26 AM2 2439SS4 NM_004833 27 EROLB 2462329 NM 0.9891 28 TRPC5 4018327 NM_012471 29 TC2N 3576704 NM 152332 30 PIP3-E 298.0449 NM_015553 31 ZMAT4 3132616 NM 024645 32 PTPRC 2373842 NM_002838 33 RHOBTB3 2820925 NM_014899

Figure 9 Patent Application Publication Oct. 27, 2016 Sheet 76 of 111 US 2016/0312305 A1

34 TMP 3976341 NM_003254 35 MPZL2 3393720 NM 144765 36 IL7R 2806468 NM 002185 37 SLC4A4 2.730746 NM_001098484 38 MYEF2 3622934 NM_016132 39 LGALS2 3960174 NM_006498 40 KCNA3 2427619 NM_002232 4. PDESA 2783596 NM_001083 42 COP1 3389450 NM_052889 43 ANK2 2740067 NM_001148 44 EPs8 3445908 NM_004447 45 PLAGl 3136178 NM_002655 46 TLR10 27661.92 NM_030956 47 IGF2BP2 2708922 NM_006548 48 PDK4 3062082 NM_002612 49 TMEM100 3763390, NM_001099640 50 SLCSA8 3467949 NM 145913 51 KLRG1 3404030 NM_005810 52 CP 2700244 NM_000096 53 RYR2 2387126 NM_001035 54 TMEM171 2815220 NM_173490 55 BHLHB2 2608725 NM_003670 56 ARNTL 332 150 NM 001178 57 GBP5 242203S NM 052942 58 CYSLTR1 401.3460 NM_006639 59 ACBD7 3279.058 NM_0010398.44 60 LYPLA1 3135567 NM_006330 61 GABBR2 3217242 NM 005458 62 TGA4 2518272 NM_000885 63 PLEKHF2 3107828 NM_024613 64 LOC401498 3166644 NM 212558 65 CASP1 3389353 NM_033292 66 MLLT3 3200982 NM_004529 67 CMAH 29.45882 NR 002174

Figure 9 Continued Patent Application Publication Oct. 27, 2016 Sheet 77 of 111 US 2016/0312305 A1

68 TPR 2608469 NM_001099952 69 GLDC 3197955 NM_000170 70 LRRN3 3019158 NM_001099660 71 TMEM156 276.6289 NM 024943 72 ATP8A1 2767378 NM_006095 73 CSGALNACT1 3126504 NM_018371 74 PYHIN1 236235. NM 152501 75 ZNF208 3.856646 ENST00000340708 76 DOCK8 3159330 NM 203447 77 JAK2 3160895 NM_004972 78 SORBS2 2796995 NM_021069 79 CD2 2353669 NM_001767 80 RHOH 2724671 NM_004310 8 PLEK 248681.1 NM 002664 82 ABCD2 3450861 NM_005164 83 PRICKLE1 345.375 NM_153026 84 KLRB1 3443804 NM_002258 85 STK17B . 2593.59 NM_004226 86 CD69 3443868 NM_001781 87 PGCP 308226 NM_016134 88 NOD1 3044072 NM_006092 89 ENTPD1 3259253 NM_001776 90 C1orf.34 2412312 NM_001080494 91. CCDC146 3009838 NM_020879 92 LRRN1 . 2608309 NM_020873 93 C12orf.35 341.0384 NM_018169 94 ANXAl 3174816 NM 000700 95 CAMK4 28.23880 NM_001744 96 EFEMP1 2554018 NM_004105 97 SPP1 2735027 NM_0010400.58 98 C17orf&7 3742627 AY358.809 99 SEPP1 2855285 NM_001093726 100 PTPN22 2428796 NM_015967

Figure 9 Continued Patent Application Publication Oct. 27, 2016 Sheet 78 of 111 US 2016/0312305 A1

Fold Rank Gene Symbol TCID P value Change SCG3 3594003 5.77E-85 6.20 2 SYT4 3805614. 9.6SE-75 4.17 3 SCG2 260.1230 3.63E-74 4.42 4 DNAJC12 3292413 5.07E-74 3.19 5 CHGB 3875179 5.06E-73 S.88 6 NEFM 3090436 729E-71 4.39 7 INA 326229 2.30E-70 3.95 8 KIAA1409 3549264 3.73E-70 2.55 9 CALCA 3364127 140E-68 5.73 10 CEACAM5 3834341 3.01E-67 5.55 11 ASCL1 3429008 403E-66 3,61 12 SNAP25 3876245 166E-65 3.59 13 RAB3C 28 0805 3.32E-65 3.53 14 SCN9A 2585.400 7.04E-62 3.02 15 RGS7 24.63227 2.08E-61 1.66 16 ST18 3135046 142E-60 2.82 17 SCGN 2898934 2.82E-60 3.54 18 PCSK1 2868044 1.02E-59. 2.76 19 NRXN1 2552643 2.31E-59 2.61 20 PRUNE2 32.10497 1.82E-58 3.59 2. C190rf30 3817651 3.45E-58 2.35 22 C6orf7 29.15571 5.01E-58 2.60 23 SLC2A12 2974935 6.94E-57 2.57 24 FMN2 2387711 1,73E-56 3.36 2S OROG9 3353876 9,70E-56 3.20 26 NOL4 3803628 75E-54 2.87 27 JAKMIP2 2880361 2.69E-54 2.35 28 DNAC6 23403SO 3.61E-54 1.98 29 SYT1 3423622 4.31E-54 3.36 30 CYP3A5 3063406 4.63E-54 1.78 31 HMP9 2841802 1.19E-53 2.68 32 GRP 3790529 1.80E-53 2,40

Figure 10 Patent Application Publication Oct. 27, 2016 Sheet 79 of 111 US 2016/0312305 A1

33 RET 3243846 3,10E-53 1.51 34 KIAA1244 2927604 9.26E-53 1.44 35 CNTN1 341 1721 4.37E-52 3.20 36 GRTA3 3989.448 1.14E-51 3.33 37 TSHZ2 38894.19 2.00E-51 2.79 38 PRUNE2 3210616 2.04E-51 3.06 39 FSTL5 27.91894 6.58E-51 3.82 40 EDN3 38.91447 9.93E-51 2.76 4. LGR5 3422144 1.11 E-50 2,72 42 PBOW 2976417 180E-50 2.78 43 1 GALNT13 251 1045 2.24E-50 3.28 44 CADPS. 267.9406 1.85E-49 1.77 45 PHYHIPL 3247977 1.88E-49 2.5 46 GRM8 307063 5,28E-49 2.00 47 CNKSR3 2980516 2,30E-48 1.22 48 MEIS2 361.8333 1.00E-47 1.99 49 HPGD 2794408 2.06E-47 3.40 50 DCX 4018218 3.69E-47 1.72 51 CA8 3137120 4,13E-47 155 52 FGF9 3480885 5.66E-47 2.32 53 DNER 2602770 5.94E-47 1.12 54 NCALD 347173 9.64E-47 2.43 55 TMEM16D 342.8333 1.65E-46 2.58 56 AMPH 3046.739 4.08E-46 1.19 57 SLC4A10 2512790 5,70E-46 3.37 58 BAALC 3110217 1.01E-45 1.31 59 TCD2525682 2525682 3.54E-45 1.06 60 KCND2 3021009 2.13E-44 2.12 61 ADCYAP1 377S906 2.25E-44 1.6 62 CACNA2D2 2675315 3.53E-43 1.43 63 REST 27284.08 4.17E43 -1.6) PCDHBO 2832423 8.03E-43 1.94 65 TMEM1.96 3040465 8.87E-43 2.51 66 BMP5 2958172 1.37E-42 3.04 Figure 10 Continued Patent Application Publication Oct. 27, 2016 Sheet 80 of 111 US 2016/0312305 A1

67 SEMA3E 3059393 1.70E-42 3.94 68 PPFLA2 34.63821 1.83E-42 2.46 69 GRA2 2749222 7.09E-42 2.32 70 CACNG2 3959.787 8.76E-42 1.90 71 PRKAR2B 3018375 1.91 E-41 2.78 72 KCNB2 303062 6.57E-41 1.26 73 PACRG 2935311 8,69E-41 1.64 74 HMGCLL1 2958117 1,08E-40 1.83 75 WASF1 2969289 2.12E-40 1.78 76 . CNTNAP2 3029900 5.87E-40 1.54 77 DDC 3.050388 5.92E-40 .24 78 FGF14 3523499 8.04E-40 1.77 79 NEFL 328271 9.6SE-40 1.89 80 MAPB 2814756 6.91 E-39 2.48 81 CPLX2 2842255 9.32E-39 1.03 82 FMOS 2433232 i.57E-38 2.36 83 CHGA 3549092 2,07E-38 1.05 CEACAM6 3834379 2.57E-38 3.14 8S CHST9 3802416 2.96E-38 2.39 86 PON3 3061964 5.03E-38 2.97 87 TSHR 3546213 5.91 E-38 -4.16 88 DNAH5 284.9056 1.67E-37 1.66 89 GAP43 263712 191E-37 2,66 90 GCH1 3565524 5.8E-37 2.77 91 KCNH8 263293 9,06E-37 1,04 92 TFF1 3933.559 2.55E-36 2.60 93 PCDHB4 2832.315 2,72E-36 1,74 94 KCNJ15 3920850 3.35E-36 -2.85 95 PON 3061942 4.75E-36 1.61 96 RMS2 3110395 8.47E-36 3.17 97 TXNDC13 3.896976 1.11 E-3S 1.77 98 GPX2 3568603 1.16E-35 2.28 99 NKAN2 2924081 140E-35 2.01 00 TMOD1 3181240 140E-35 2.35

Figure 10 Continued Patent Application Publication Oct. 27, 2016 Sheet 81 of 111 US 2016/0312305 A1

Rank Gene Symbol TC) RefSeq, NRCAM 3067.478 NM_001037132 DOCK9 3522398 NM_015296 CAMK2N1 2400177 NM_018584 C6orf168 29661.93 NM_032511 SCEL 3494.629 NM 144777 SPA1 L2 2460817 NM_020808 L1RAP 2657831 NM_002182 PPM2c 3107342 NM_018444 RHOBTB3 2820925 NM_014899 10 AMOT 408.454 NM_133265 11 SDC4 3907234 NM_002999 2 MET 3020343 NM_001 127500 13 DCBLD2 2686023 NM_080927 14 SYTL5 3973891 NM_1387so 15 AHNAK2 3581221 NM_138420 16 MYHO 3744463 NM_005964 17 TCD2526806 2526806 unknown 18 TACSTD2 2414958 NM_002353 19 PROS1 2685304 NM_000313 20 ERBB3 3417249 NM_001982 21 EPS8 3445908 NM_004447 22 XPR 23701.23 NM_004736 23 KRT19 3757108 NM_002276 24 7A5 3040518 NM 182762 25 FN1 2598261 NM 212482 26 GABBR2 3217242 NM_005458 27 TRAK2 2594812 NM_015049 28 GABRB2 288484.5 NM_021911 29 GALNT7 2751936 NM_017423 30 IGFBP6 3415744 NM 002178 31 NELL2 345,814 NM_006159 32 SGEF 2648535 NM_01.5595 33 SLC47A, 373951 NM_018242

Figure 11 Patent Application Publication Oct. 27, 2016 Sheet 82 of 111 US 2016/0312305 A1

34 PDZRN4 3411810 NM 013377 35 MPZL2 3393720 NM 144765 36 CMYA5 2817464 NM 153610 37 ARMCX6 4015838 NM_019007 38 SLC34A2 2721959 NM_006424 39 MPPED2 3367673 NM_001584 40 TUSC3 3087167 NM_006765 41 DTNA 3784208 NM_032975 42 FAM176A 2560625 NM 032181 43 CSorf28 2855578 BCO13351 44 CYSLTR2 3489,38 NM_020377 45 S100A5 4045589 NM_002962 46 PDE5A 2783596 NM_001083 47 KCNJ2 3733275 NM_000891 48 AK1 3226138 NM_000476. 49 LIPH 2708855 NM_139248 50 MPP7 328260 NM 173496 S1 CSNK1G3 2826550 NM_004384 S2 ZCCHC16 3987607 NM 001004308 S3 PSD3 31269) NM_015310 S4 BHLHB2 2608725 NM_003670 55 EGFR 3002640 NM 0.05228 56 SERPINA1 3577612 NM 001002236 57 ITGA3 3726154 NM_002204 58 CSGALNACT1 3.126504 NM 018371 59 CH3L1 24S1593 NM_001276 60 METTL7B 3416895 NM 152637 61 TGFA 255.8612 NM_003236 62 NAB2 . 34.17809 NM 005967 63 NFATC3 3666033 NM 173163 64 NPC2 3571904 NM_006.432 65 GGCT 3044129 ENST00000275428 66 TPO 2466554 NM_000547 67 HGD 4047070 NM_000187

Figure 11 Continued Patent Application Publication Oct. 27, 2016 Sheet 83 of 111 US 2016/0312305 A1

68 GMAP5 3031573 NM 018384 69 PKHD1 Ll 311 1561 NM 177531 70 ALDH3A2 3714068 NM_001031806 71 PRR15 2994.981 NM 175887 72 HRASLS3 3376529 NM_007069 73 ZCCHC12 3988596 NM_173798 74 STK32A 2834282 NM_001112724 75 ANK2 2740067 NM_001148 76 SORBS2 2796995 NM021069 77 ITGA2 280924S NM_002203 78 MYEF2 3622934 NM_016132 79 SYNE1 2979871 NM_182961 80 PLEKHA4 3867458 NM_020904 81 PLCD3 3759587 NM_133373 82 LAMB3 2453793 NM_001017402 83 FAM43A 2658785 NM_153690 84 TPD52L1 2924330 NM_001003395 85 CLDN 27105.99 NM_021101 86 B3GNT3 3824S96 NM_014256 87 KIAA1217 3238962 NM_019590 88 MAP2 2525533 NM_002374 89 LRP1B 2578790 NM_018557 . 90 ITPR 2608469 NM_001099952 91 CARD8 3866958 NM_014959 92 DGKI 307492 NM_004717 93 LFR 285.4092 NM 002310 94 DOCK8 3159330 NM 203447 95 C9orf6 3173974 NM_004816 96 GPR98 2819779 NM_032119 97 TFF3 3933S36 NM 003226 98 ERO1LB 2462329 NM 019891 99 ARHGAP24 2734421 NM_001025616 100 CDON 3396770 NM_016952 101 TBC1D4 3518086 NM014832

Figure 11 Continued Patent Application Publication Oct. 27, 2016 Sheet 84 of 111 US 2016/0312305 A1

102 LRP2 2586038 NM 004.525

Figure 11 Continued Patent Application Publication Oct. 27, 2016 Sheet 85 of 111 US 2016/0312305 A1

Ra nk Gene Symbol TCD . TGFA 2S58612 PROS1 2685304 MET 3020343 DPP4 2584018 GALNT7 2751936 TPO 2466554 SDC4 3907234 FABP4. 3142381 KIT 2727587 ELIMO 3046197 CDH3 3666366 CAMK2N. 2400177 KRT19 3757108 SCEL 3494.629 TFF3 3933536 LRPB 2578790 CITED1 4012178 PLA2R1 2583.374, SK32A 2834282 IL1RAP 2657831 LGALS3 3536706 GPR155 2587790 MPPED2 3367673 C6orf 68 2966193 METTL7B 3416895 NPC2 35.71904 NAB2 3417809 KHDRBS2 2959039 LIPH 270885.5 CXorf27 39.73891 FN1 259826 EPS8 3445908 ZMAT4 3132616

Figure 12 Patent Application Publication Oct. 27, 2016 Sheet 86 of 111 US 2016/0312305 A1

34 SLC26A4 3018605 35 TNFRSF11B 315045S 36 ANGPTL 2445982 37 NFATC3 3666033 38 ITPR1 2608469 39 GABRB2 2884845 40 TBC1D4 358086 41 SCG5 3587495 42 CYP1B1 2548699 43 HMGA2 3420316 TC2N 3576704 45 ATP10D 2726072 46 RAG2 336993 47 DUSP6 3464860 48 ERO1 LB 2462329 49 SCNNA 3441885 50 ABCC3 3726691 51 ARHGAP24 2734421 52 SEMA3D 305.9667 53 CH3L1 2451593 54 SPOCK1 2876897 55 PDE5A 2783596 56 MYH10 3744463 57 SERPINA1 3577612 58 SPA12 2460817 59 ITM2A 4013549 60 TNFAIP8 282.5629 61 MYEF2 3622934 62 KCNJ2 3733275 63 CRABP1 3603295 64 - MATN2 3108.526 65 CLDN16 2657808 66 NRCAM 30674.78 67 HEY2 29244.92

Figure 12 Continued Patent Application Publication Oct. 27, 2016 Sheet 87 of 111 US 2016/0312305 A1

68 PTTG1 283820 69. SPINT1 359064 70 CDC27 3760625 71 NOD1 3044072 72 KPNAS 2922840 73 DYNLT1 298.1874 74 ODZ. 4020655 : 75 GABBR2 3217242 76 SLC33A1 2701927 77 UPP1 3000953 78 AUTS2 3006572 79 SLC34A2 2721959 80 MFGE8 3638204 81 RXRG 2442008 82 KLF8 3978943 83 ANK2 2740067 84 TM7SF4 3110608 85 ZCCHC16 3987607 86 FNOC4 2545.953 87 GLT8D2 34,68888 88 GDF15 3824993 89 GIMAPs 3031466 MAP2 2525533 91. TMP1 3976341 92 PGCP 3.108226 93 KLK7 3868783 94 DNASE1L3 2678298 95 ANKRD12 3778252 96 CLDN1 27105.99 97 SERINC2 2328273 98 HSD17B6 347703 TSC22D1 35,2294 100 TRPCS 4018327

Figure 12 Continued Patent Application Publication Oct. 27, 2016 Sheet 88 of 111 US 2016/0312305 A1

TC) Gene Symbol Subtype 1 Subtype 2 Subtype 3 3132616 ZMAT4 FAFVPTC FA PTC FVPTC NHP 2809793 GZMK FC LCT FVPTCLCT HC LCT 3444086 KLRK FC LCT FVPTC LCT HC LCT 2959039 KHDRBS2 FAFC FA HC HC NHP 2657808 CLDN16 FAFC FA PTC LCT PTC 4020655 ODZ1 FA FC FVPTCLCT LCT PTC 3692999 MT1G FAMTC FA PTC MTC NHP 27105.99 CLDN1 FAFC FA PTC NHP PTC 3.536706 LGALS3 FA FVPTC FA PTC NHP PTC 3577612 SERPDNA FA FVPTC FA PTC NHP PTC 2727587 KIT FA FVPTC FVPTC NHP NHP PTC 3367673 MPPED2 FA PTC FVPTC NHP NHP PTC 288484.5 GABRB2 FA PTC LCT PTC NHP PTC 268S304 PROS1 FA PTC LCT PTC NHP PTC 356,4210 PYGL ATC FA ATC LCT 3168508 MELK ATC FA ATC NHP 3913483 TCFL5 FAFC FA FVPTC 3726691 ABCC3 FA FC FA PTC 36622.01 MTH FA FC FA PTC 3369931 RAG2 FA FC FA PTC 2573.570 TFCP2L1 FA FC FA PTC 2466SS4 TPO : FAFC FA PTC 3944404 APOL1 FA FVPTC FA PTC 34S1814 NELL2 FA FVPTC FA PTC 3592214 DUOX1 FA HC FVPTCLCT 2809810 GZMA FC LCT FVPTC LCT 3018605 SLC26A4 FA FC FVPTC NHP 3755862 KZF3 FA PTC HC LCT 2373842 PTPRC FC LCT HC LCT 344389 CLEC2B FVPTCLCT HC LCT 303556 GMAP2 FVPTC LCT HC LCT 303517 GMAP7 FVPTC LCT HC LCT 3160895 JAK2 FVPTC LCT HC LCT

Figure 13 Patent Application Publication Oct. 27, 2016 Sheet 89 of 111 US 2016/0312305 A1

3666033 NFATC3 FVPTC LCT HC LCT 3417703 HSD17B6 FA HC HC NHP 3875179 CHGB FA MTC LCT MTC 2834282 STK32A FA FC LCT PTC 2751936 GALNT7 FA PTC LCT PTC 2708855 LPH FA PTC LCT PTC 3393.720 MPZL2 FA PTC LCT PTC 3464,860 DUSP6 FVPTCLCT LCT PTC 3416895 METTL7B FVPTCLCT LCT PTC 2711225 ATP3A4 FVPTCLCT MTC NHP 3364127 CALCA LCT MTC MTC NHP 2526806 2526806 FA PTC NHP PTC 343O462 BTBD1 FA PTC NHP PTC 3086809 C8orf79 FA PTC NHP PTC 3396770 CDON FA PTC NHP PTC 258.408 DPP4 FA PTC NHP PTC 2598.261 FN FA PTC NHP PTC 2378068 GOS2 FA PTC NHP PTC 392,5639 NRP1 FA PTC NHP PTC 3270270 PTPRE FA PTC NHP PTC 2721959 SLC34A2 FA PTC NHP PTC 2.730746 SLC4A4 FA PTC NHP PTC 2796995 SORBS2 FA PTC NHP PTC 3976341 TMP FA PTC NHP PTC 2455933 ESRRG FVPTC NHP NHP PTC 2819779 GPR98 FVPTC NHP NHP PTC 2578790 LRP1B FVPTC NHP NHP PTC 2586038 LRP2 FVPTC NHP NHP PTC 3108.526 MATN2 FVPTC NHP NHP PTC 4014029 RPS6KA6 FVPTC NHP NHP PTC 296.177 COL12Al ATC LCT 3590014 CASCS ATC NHP 3258444 CEP55 ATC NHP 3565663 DLG7 ATC NHP

Figure 13 Continued Patent Application Publication Oct. 27, 2016 Sheet 90 of 111 US 2016/0312305 A1

28.38656 HMMR ATC NHP 32.581.68 KDF11 ATC NHP 33 12490 MK67 ATC NHP 3776139 NDC80 ATC NHP 3590388 NUSAP1 ATC NHP 3881443 TPX2 ATC NHP 2406391 2406391 FA FC 2445982 ANGPTL1 FAFC 3459722 AVPRA FA FC 3124344 C3orf5 FAFC 3.07234 C3orf39 FA FC 301.0503 CD36 FA FC 3580769 CKB FA FC 360329S CRABP1 FAFC 2336891 DIO1 FA FC 3384,704 DLG2 FA FC 2678298 DNASE1L3 FA FC 298.1874 DYNLT1 FAFC 30O8144 EIF4H. FA FC 2462329 ERO1LB FA FC 4027639 F8 FAFC 3142381 FABP4. FA FC 3576749 FBLNS FA FC 3937967 FLJ26O56 FAFC 3393479 FXYD6 FAFC 3197140 GLIS3 FA FC 3250278 HK1 FA FC 2770469 IGFBP7 FAFC 2452440 KLHDC8A FA FC 3067302 LAMB1 FAFC 28S4092 LIFR FAFC 374,5525 LOC388335 FAFC 3244055 LOC4399.1 FAFC 378.8097 MAPK4 FA FC

Figure 13 Continued Patent Application Publication Oct. 27, 2016 Sheet 91 of 111 US 2016/0312305 A1

258 000 NEB FAFC 298.0449 PIP3-E FAFC 29,55827 PLA2G7 FAFC 3009229 POR FAFC 2349848 PRMT6 FA FC 3555675 RNASE1 FAFC 2984884 RNASET2 FA FC 3363868 RRAS2 FA FC 3899.173 RRBP1 FA FC 2387126 RYR2 FAFC 336S 136 SERGEF FAFC 2529421 SGPP2 FAFC 392.442 SH3BGR FAFC 2319340 SLC25A33 FAFC 31 14832 SQLE FAFC 2932508 TAM2 FAFC 3943504 TIMP3 FAFC 33884.38 TRPC6 FA FC 2S384.80 TSSC1 FAFC 3441941 VAMP1 FAFC 2331558 BMP8A FA HC 2648991 KCNAB1 FA HC 2931172 IYD FA MTC 366.1718 LPCAT2 FAMTC 38894.19 TSHZ2 FA MTC 3040518 7AS FA PTC 299,233 AHR FA PTC 324.4622 ALOXS FA PTC 3627248 ANXA2 FA PTC 38.48039 C3 FA PTC 27391.60 CCDC109B FA PTC 2902844 CFB FA PTC 24S1593 CH3L1 FA PTC 312906S CLU FA PTC

Figure 13 Continued Patent Application Publication Oct. 27, 2016 Sheet 92 of 111 US 2016/0312305 A1

3335894 CST6 FA PTC 3385769 CTSC FA PTC 3634811 CTSH FA PTC 2773434 CXCL2 FA PTC 3973 891 CXorf27 FA PTC 254.8699 CYP1B1 FA PTC 3489138 CYSLTR2 FA PTC 3768535 FAM20A FA PTC 3306984 GPAM FA PTC 3727.583 HLF FA PTC 3820443 ICAM1 FA PTC 3415744 IGFBP6 FA PTC 2657831 IL1RAP FA PTC 378787 KATNAL2 FA PTC 2764.192 KIAA0746 FA PTC 3978943 KLF8 FAPTC 3757108 KRT 9 FA PTC 2634.09 NFKBIZ. FA PTC 26390S4 PARP14 FA PTC 311561 PKHD1L1 FA PTC 3977067 PLP2 FA PTC 3426502 PLXNC1 FA PTC 3930360 RUNX1 FA PTC 2908762 RUNX2 FA PTC 306559 SLC26A7 FAPTC 2827645 SLC27A6 FA PTC 3907 190 SLP FA PTC 24.91271 TMSB10 FA PTC 2353669 CD2 FC LCT 2440354. CD48 FC LCT 2326463 CD52 FC LCT 2773947 CXCL9 FC LCT 285.4327 FYB FC LCT 2903401 HLA-DPB FC LCT

Figure 13 Continued

Patent Application Publication Oct. 27, 2016 Sheet 94 of 111 US 2016/0312305 A1

3866958 CARD8 HC LCT 3389353 CASP1 HC LCT 3393744 CD3D HC LCT 2635741 CD96 HC LCT 31.87577 CEP110 HC LCT 3815399 CNN2 HC LCT 3629811 DENND4A HC LCT 3159330 DOCK8 HC LCT 2424524 DPWD HC LCT 2739303 EGF HC LCT 2997.907 EPDR1 HC LCT 3397589 ETS HC LCT 2422035 GBP5 HC LCT 3031573 GMAPS HC LCT 398262 GPR174 HC LCT 2362,394 FI6 HC LCT 3918447 FNAR2 HC LCT 28.06468 L7R HC LCT 4013S49 ITM2A HC LCT 3404030 KLRG1 HC LCT 2508520 KYNU HC LCT 2531310 LOC93349 HC LCT 4037.595 ND1 HC LCT 32.56590 PAPSS2 HC LCT 3772525 PSCD1 HC LCT 2362,351 PYHN1 HC LCT 2592356 STAT4 HC LCT 3576704 TC2N HC LCT 3176209 TLE4 HC LCT 2579.572 ZEB2 HC LCT 33 19898 ZNF143 HC LCT 3197231 C9orf68 HC NHP 2750627 CPE HC NHP 3108226 PGCP HC NHP

Figure 13 Continued Patent Application Publication Oct. 27, 2016 Sheet 95 of 111 US 2016/0312305 A1

3301713 BLNK LCT MTC 3110395 RMS2 LCT MTC 3594.003 SCG3 LCT MTC 2966193 C6orf168 LCT PTC 3445908 EPS8 LCT PTC 2708922 IGF2BP2 LCT PTC 31.2619.1 PSD3 LCT PTC 3183757 RAD23B LCT PTC 2711205 ATP1 3A4 MTC NHP 34,86096 FREM2 MTC NHP 2734421 ARHGAP24 NHP PTC 2763278 GPR125 NHP PTC 3625271 RAB27A NHP PTC 305.9667 SEMA3D NHP PTC

Figure 13 Continued Patent Application Publication Oct. 27, 2016 Sheet 96 of 111 US 2016/0312305 A1

Subtype Simplified Sample D Sample Type Pathology Pathology . A007251 FNA FA B AOOl7252 FNA FA B AO017255 FNA FA B AO017256 FNA FA B A0017264 FNA FA B AOO17267 FNA FA B AO017272 FNA - FA B AO017285 FNA FA B AOO17289 FNA FA B AO017291 FNA FA B A0017292 FNA FA B A001.7298 FNA FA B AO017978 FNA FA B AO017986 FNA FA B AO017987 FNA FA B AO017989 FNA FA B AO017991 FNA FA B AOO17995 FNA FA B A001 8000 FNA FA B AO08004 FNA FA B A0018006 FNA FA B A0018008 FNA FA B A001800 FNA FA B A0018011 FNA FA B A0018018 FNA FA B AO017258 FNA NHP B AOO1726S FNA NHP B A001.7271 FNA NHP B AO017275 FNA NHP B A0017276 FNA NHP B A0017278 FNA NHP B A0017280 FNA NHP B

Figure 14 Patent Application Publication Oct. 27, 2016 Sheet 97 of 111 US 2016/0312305 A1

A001729S FNA A0017296 FNA A0017297 FNA A001 7299 FNA AO017979 FNA AO017980 FNA A0017983 FNA A0017984 FNA A0017985 FNA AO017988 FNA A0017993 FNA AO017994 FNA A0017997 FNA AO017998 FNA A0018009 FNA AOO18020 FNA AO08021 FNA A0018022 FNA A0017270 FNA FC AO07294 FNA FC A007.981 FNA FC A008016 FNA FC AO08023 FNA FC A0018025 FNA FC A0017269 FNA FVPTC AO017279 FNA FVPTC A0017982 FNA FVPTC AO017999 FNA FVPTC AO017268 FNA MTC AO017250 FNA PTC AO0172S3 FNA PTC AO017254 FNA PTC AO017257 FNA PTC AO017266 FNA PTC

Figure 14 Continued Patent Application Publication Oct. 27, 2016 Sheet 98 of 111 US 2016/0312305 A1

AO07273 FNA PTC AO017274 FNA PTC AO017281 FNA PTC AO017282 FNA PTC A0017284 FNA pTC AO017286 FNA PTC A0017290 FNA PTC A007293 FNA PTC AO017990 FNA PTC AO017992 FNA PTC A007996 FNA PTC A0018001 FNA PTC AO08002 FNA PTC AO08003 FNA PTC A001800S FNA PTC AOO18007 FNA PTC A0018012 FNA PTC A0018014 FNA PTC A001801S FNA PTC AO08017 FNA PTC AO08019 FNA PTC A0018024 FNA PTC A0018027 FNA PTC

Figure 14 Continued Patent Application Publication Oct. 27, 2016 Sheet 99 of 111 US 2016/0312305 A1

Sample Simplified Sample ID Type Subtype Pathology R101 FNA PTC M miR102 FNA NHP B miR103 FNA PTC M miR104 FNA BN B miROS FNA BN B miR106 FNA LCT B miR107 FNA LCT B miR108 FNA BN B miR109 FNA PTC M miR110 FNA FVPTC M miR111 FNA LCT B miR112 FNA PTC M miR 13 FNA BN B miR114 FNA NHP B miR 15 FNA CN B miR) 16 FNA y B B miR17 FNA NHP B miR118 FNA CN B miR119 FNA PTC M miR120 FNA PTC M miR12 FNA non-diagnostic non-diagnostic miR122 FNA NHP B miR123 FNA NHP B miR124 FNA NHP B

Figure 15