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Supplementary Appendix Supplementary Appendix Genomic Analysis of Thymic Epithelial Tumors Identifies Novel Subtypes Associated with Distinct Clinical Features Hyun-Sung Lee1, Hee-Jin Jang1, Rohan Shah1, David Yoon1, Masatsugu Hamaji2, Ori Wald1, Ju-Seog Lee3, David J. Sugarbaker1, Bryan M. Burt1 1 Table of Contents Section Page Supplementary Methods 3 Supplementary Figure Figure S1 Genomic positions of amplifications and deletions in TCGA TETs 4 Hierarchical Clustering Analysis of mRNA Expression Data in Patients Figure S2 5 with TET (n=120) Distribution of TET molecular subtypes and 3-D plot of principal Figure S3 6 component analysis and molecular subtypes of TETs Survival of TCGA TET cohort based on Masaoka staging system to Figure S4 7 check the quality of clinical data Figure S5 GTF2I mutation and mRNA expression of GTF2I across 30 types of 8 TCGA cancer Supplementary Table Table S1 Subtype-specific mRNAs in thymic epithelial tumors 9 Table S2 Clinicopathologic Characteristics of Patients 22 Table S3 Univariable Cox Regression Analysis of molecular subtypes and 23 Disease-Free Survival in the TCGA TET Sets (n=120) Table S4 List of 220 GTF2I target gene set using known transcription factor 24 binding site motifs within the TRANSFAC® predicted transcription factor targets dataset 2 SUPPLEMENTARY METHODS Justification of Decision-Tree Approach through mutual exclusivity and principal component analysis in molecular subtypes of TETs The test for mutual exclusivity applied to groups defined by GTF2I mutation, T cell signaling signature, and SCNA revealed that each subgroup was mutually exclusive (P=3.7x10-14) (Supplementary Figure S2A). Similarly, a 3D-plot of PCA demonstrated that the molecular subgroups could be distinctly separated by GTF2I mutation, T cell signaling, and SCNA (Supplementary Figure S2B). The distribution tails of GTF2I mutation and T cell signaling signature exhibited a mutually exclusive pattern (P=1.4x10-6), and thus identified the groups of samples in the GTF2I and TS groups, respectively. T cell signaling and SCNA were also mutually exclusive (P=2.4x10-8), but GTF2I mutation and SCNA were less significant (P=0.056). Herein, we prioritized the GTF2I mutational status to generate a clinically relevant model since unsupervised clustering and PCA of mRNA data revealed that GTF2I mutation plays a crucial role in classifying TET. Thus, a decision tree algorithm was created to categorize the 120 TET samples into four subtypes using an approach that could more readily be applied to TET in clinical care (Figure 1A). 3 4 5 6 7 8 Supplementary Table S1. Subtype-specific mRNAs in thymic epithelial tumors. GTF2I TS CS CIN Fold Fold Fold Fold Expression Subtype GTF2I Change TS Change CS Change CIN Change UP 1 TBX1 138.89 PTCRA 27.03 UPF0639 10.00 PRLR 14.49 2 AACSL 107.53 DNTT 26.32 FCRLA 9.09 MEGF11 13.51 3 KLK8 83.33 CD1B 21.28 CHST8 8.33 TMEM40 13.33 4 DKFZp686A1627 76.92 RAG2 20.00 FCRL2 8.33 FOXA1 10.75 5 FBN3 76.92 PRKCG 19.61 SLITRK4 8.33 LANCL3 10.64 6 AQP5 71.43 CCR9 18.87 CHL1 7.69 PITX1 10.20 7 IRX4 71.43 ARPP21 18.52 F5 7.69 CKMT1B 10.10 8 PHEX 66.67 SLC7A3 17.86 BARX2 6.67 CBLC 10.00 9 IRX2 55.56 C19orf77 16.13 CD22 6.25 GPR144 10.00 10 C1QTNF9B 50.00 ARL5C 15.87 FCRL1 6.25 ENTPD3 9.09 11 SEMA3D 50.00 KCNJ4 15.63 HAS2 6.25 PHF21B 9.09 12 CLCNKB 41.67 CD1A 15.38 SELE 6.25 WDR69 9.09 13 SPOCK3 37.04 CD1E 15.15 FAM13C 5.26 MYO3B 8.33 14 WDR72 34.48 CHRNA3 14.93 PLXNA4 5.26 PDZK1IP1 8.33 15 COL9A3 33.33 C10orf129 14.29 ADAMTS14 5.00 DHDPSL 7.69 16 GPR81 33.33 DPPA4 14.08 ABCA6 4.76 GRHL3 7.69 17 ZNF560 32.26 CFC1B 13.51 CLEC17A 4.76 MOCOS 7.69 18 TYRP1 30.30 MAL 13.33 RGS7 4.76 CKMT1A 7.14 19 GPR158 28.57 UGT3A2 13.33 SLC22A3 4.76 CPLX3 7.14 20 SCUBE3 27.78 TMIGD2 13.16 KCNJ15 4.55 FAM196B 7.14 21 NTF3 27.03 AOX2P 12.99 LPPR4 4.55 PIK3C2G 7.14 22 SEMA3E 27.03 HHIP 12.35 POU2AF1 4.17 POF1B 7.14 23 ADAMTS20 26.32 ZP1 12.20 CSF3 4.00 SMOC1 7.14 24 GJB7 26.32 PRL 11.90 VSIG1 3.85 EVPL 6.67 25 SCUBE1 25.64 RORC 11.90 ECM2 3.57 NCAM2 6.67 26 VGLL3 25.00 CELF5 11.63 HSD11B1 3.57 SRPX2 6.67 27 CLDN8 24.39 PON1 11.63 STAP1 3.57 ALDH1A1 6.25 28 TMEM59L 23.81 CD1C 11.36 ADAMTS4 3.45 C1orf175 6.25 29 TULP1 23.81 MGC29506 11.11 GIPR 3.45 CEND1 6.25 30 SOHLH1 22.73 HMHB1 10.64 SLC12A8 3.45 CYP4F3 6.25 31 PDGFRL 22.22 CXorf49B 10.00 WNT7A 3.45 DGCR9 6.25 32 PRAME 21.28 ELOVL4 10.00 CDKN2B 3.33 DNAH5 6.25 33 PCDHGA11 20.83 GPR44 10.00 CNR2 3.33 KCND3 6.25 34 ANKRD26P1 20.41 LCT 10.00 PTGFR 3.33 NWD1 6.25 35 AQP6 20.00 PRMT8 10.00 RGS16 3.33 AIM1L 5.88 36 THSD4 19.23 TMSB15A 10.00 EBF2 3.23 C12orf54 5.88 37 C5orf38 18.52 VPREB1 10.00 PDE4B 3.13 C19orf45 5.88 9 38 GDF5 18.52 HEMGN 9.09 C6 2.94 CADPS 5.88 39 GPR98 18.18 HRK 9.09 LBP 2.94 DCST2 5.88 40 SLITRK5 18.18 PADI4 9.09 SERPINE2 2.94 IGSF9 5.88 41 COL11A1 17.86 SH2D1A 9.09 TLR10 2.94 MARK1 5.88 42 MYH6 17.86 SMPD3 9.09 IL33 2.86 OSBPL6 5.88 43 COL2A1 17.24 STK32B 9.09 P2RY10 2.86 PGBD5 5.88 44 GPR88 17.24 ABCG4 8.33 ADAM19 2.78 RAP1GAP 5.88 45 SLCO1A2 17.24 ASPDH 8.33 SIGLEC6 2.70 RIMKLA 5.88 46 CCDC144NL 16.95 CD3D 8.33 PDE3B 2.56 TMEM163 5.88 47 FAM132A 16.95 CPA5 8.33 USP26 2.56 ZBP1 5.88 48 SLPI 16.95 FSD1 8.33 DOK3 2.50 FAM155B 5.56 49 FOXI2 16.67 GLYATL1 8.33 PALLD 2.50 GPT 5.56 50 RBM46 16.67 HKDC1 8.33 CXCR7 2.44 IL1RN 5.56 51 DLK2 16.13 HOXA10 8.33 DLEC1 2.44 NCKAP5 5.56 52 KLK7 16.13 NR5A1 8.33 HIF1A 2.44 S1PR5 5.56 53 SGCA 16.13 ODZ1 8.33 IRAK2 2.44 WFDC5 5.56 54 NTS 15.87 PRSS3 8.33 MAP1LC3C 2.44 ALDH4A1 5.26 55 TDGF1 15.87 TSHR 8.33 PALMD 2.44 EMX1 5.26 56 C16orf89 15.63 APOA1 7.69 CD180 2.38 GPR37 5.26 57 IL17RD 15.63 C17orf67 7.69 GSDMC 2.38 MAPK8IP2 5.26 58 LPHN3 15.63 C2orf85 7.69 SP140 2.38 STC2 5.26 59 GFRA3 15.38 CMTM2 7.69 SLFN12L 2.33 TMEM132A 5.26 60 KRT14 15.38 CPLX1 7.69 CD44 2.27 TMEM145 5.26 61 MAB21L2 15.15 E2F2 7.69 LDB2 2.27 ANKRD2 5.00 62 C3orf32 14.93 HIST1H3G 7.69 CYSLTR1 2.22 C3orf14 5.00 63 NGEF 14.93 KIAA1257 7.69 EVI2B 2.22 FAM84A 5.00 64 PCDHGA12 14.93 MCHR1 7.69 SAMD9L 2.22 GRID1 5.00 65 CRLF1 14.71 SLAMF1 7.69 CCDC88C 2.17 SRPK3 5.00 66 SYT1 14.71 C2orf48 7.14 EMB 2.08 CAPNS2 4.76 67 WNT2 14.49 CREB3L3 7.14 NCOA7 2.08 LPIN3 4.76 68 CYS1 14.29 CXorf65 7.14 BLNK 2.04 OAS1 4.76 69 EDAR 14.29 FGFBP2 7.14 PCDHA1 4.76 70 FBN2 14.29 GRAP2 7.14 PLIN4 4.76 71 FOLR1 14.29 HOXA9 7.14 POU3F1 4.76 72 GDF1 14.29 KIAA0087 7.14 TRAM1L1 4.76 73 IGFBP6 14.08 LEF1 7.14 ACOT11 4.55 74 KC6 14.08 SH3GL3 7.14 AHNAK2 4.55 75 BCAM 13.89 SPTA1 7.14 ARNT2 4.55 76 FCN2 13.89 TOX2 7.14 DIO2 4.55 77 CHRM3 13.51 ADA 6.67 MCOLN2 4.55 78 KLK10 13.33 C10orf50 6.67 C14orf50 4.35 10 79 SPINK5 13.33 C1orf228 6.67 CECR2 4.35 80 C8orf31 12.66 CD38 6.67 CHRNB2 4.35 81 GAL3ST3 12.66 EVPLL 6.67 CYP4F11 4.35 82 CXCL1 12.50 HIST1H3C 6.67 EGF 4.35 83 UTS2R 12.50 HIST1H3F 6.67 FAM78B 4.35 84 CNTN4 12.05 HIST2H2AC 6.67 HCN1 4.35 85 LASS1 12.05 JAKMIP2 6.67 MSLNL 4.35 86 AMOTL2 11.90 MYB 6.67 TMEM151B 4.35 87 TDGF3 11.90 MYO7B 6.67 TUFT1 4.35 88 ERBB4 11.76 NEIL3 6.67 ABCA9 4.17 89 AOX1 11.49 SIT1 6.67 C1orf53 4.17 90 C8orf84 11.49 SPSB4 6.67 CNTNAP4 4.17 91 CRYAB 11.49 TCF7 6.67 ENAH 4.17 92 NEBL 11.49 XPNPEP2 6.67 HDAC9 4.17 93 C14orf39 11.36 AURKB 6.25 MANEAL 4.17 94 ZNF208 11.36 BFSP2 6.25 SPIRE2 4.17 95 CLDN10 11.24 CD247 6.25 KLF4 4.00 96 CPAMD8 11.24 CD3E 6.25 OASL 4.00 97 PRSS12 11.24 CD8B 6.25 PTK6 4.00 98 COL28A1 11.11 CENPA 6.25 LRRC16B 3.85 99 SLC16A12 11.11 CRABP1 6.25 LUZP2 3.85 100 SNCAIP 11.11 FAM57B 6.25 MPV17L 3.85 101 FN1 10.87 GFI1 6.25 NKAIN1 3.85 102 ITGB8 10.87 HIST1H2AJ 6.25 SPR 3.85 103 LIPH 10.87 RETN 6.25 TMEM38A 3.85 104 MLXIPL 10.87 SLC23A1 6.25 GPRIN1 3.70 105 SLC34A2 10.87 TMPRSS9 6.25 KIAA1211 3.70 106 GJB6 10.75 TREML2 6.25 LMAN1L 3.70 107 ZSCAN4 10.75 ARRDC5 5.88 LYPD5 3.70 108 TFAP2A 10.64 BIRC5 5.88 PTPRH 3.70 109 CYP39A1 10.53 C17orf50 5.88 SLC13A3 3.70 110 ICAM5 10.31 C22orf15 5.88 TCTE1 3.70 111 MAOA 10.31 CAMK4 5.88 C1orf182 3.57 112 SCN4B 10.31 CCL17 5.88 C2orf66 3.57 113 ANKRD56 10.20 CYP2U1 5.88 FAAH2 3.57 114 GAP43 10.20 GSTM5 5.88 FAM195A 3.57 115 HTR2C 10.20 GTSF1 5.88 FRK 3.57 116 FLRT2 10.10 HIST1H2AH 5.88 RAPGEFL1 3.57 117 CXCL6 10.00 HIST1H3J 5.88 TACR2 3.57 118 ID4 10.00 LCNL1 5.88 ANKRD9 3.45 119 MAGEL2 10.00 LIPC 5.88 CADPS2 3.45 11 120 PCDHGA6 10.00 MME 5.88 CSRP1 3.45 121 SPERT 10.00 SPNS3 5.88 MYRIP 3.45 122 C4orf31 9.09 TLX2 5.88 SRD5A1 3.45 123 CTGF 9.09 BEST3 5.56 TLR5 3.45 124 CYP27C1 9.09 C14orf64 5.56 ACCN1 3.33 125 FAM71E2 9.09 CA6 5.56 B3GNT8 3.33 126 GPM6A 9.09 CACNA1F 5.56 CDC42EP4 3.33 127 GRM4 9.09 CAPSL 5.56 DSC1 3.33 128 KANK4 9.09 CD3G 5.56 FOSL2 3.33 129 KCNS1 9.09 CDC20 5.56 GAS2L1 3.33 130 LYPD1 9.09 CDC25C 5.56 MST1R 3.33 131 PCDH15 9.09 CHI3L2 5.56 STAP2 3.33 132 PCDHGB7 9.09 CNIH2 5.56 C10orf55 3.23 133 SCARA3 9.09 FAM64A 5.56 DAB1 3.23 134 SGCE 9.09 HIST1H2AL 5.56 NEURL1B 3.23 135 SLC5A12 9.09 HIST1H2BL 5.56 PPEF1 3.23 136 SLITRK2 9.09 HIST1H3B 5.56 SHOX2 3.23 137 SP6 9.09 KCNF1 5.56 SLCO3A1 3.23 138 SYT17 9.09 LINGO4 5.56 TMEM144 3.23 139 TMEM130 9.09 LRRC26 5.56 ADAM15 3.13 140 TRIL 9.09 MKRN3 5.56 BATF2 3.13 141 WNT2B 9.09 MND1 5.56 C8orf73 3.13 142 ADAMTS5 8.33 NDST3 5.56 EPHB2 3.13 143 C10orf82 8.33 NECAB1 5.56 STOML3 3.13 144 CCDC68 8.33 PRSS1 5.56 CARD14 3.03 145 DCHS2 8.33 PVRIG 5.56 HSD3B7 3.03 146 DZIP1 8.33 SEPT1 5.56 IQSEC2 3.03 147 FAM83A 8.33 SLC22A16 5.56 PLCH2 3.03 148 KLHL14 8.33 SLIT1 5.56 PYGO1 3.03 149 LEPR 8.33 SPC25 5.56 RGMA 3.03 150 LRP4 8.33 TRAT1 5.56 SIK1 3.03 151 MN1 8.33 UMODL1 5.56 ANK1 2.94 152 NRK 8.33 UPB1 5.56 RNF148 2.94 153 PCDHGA2 8.33 ADORA2A 5.26 SLC34A1 2.94 154 PP14571 8.33 C12orf42 5.26 TNFSF10 2.94 155 PRUNE2 8.33 C21orf128 5.26 FAM108C1 2.86 156 PTPRZ1 8.33 C22orf34 5.26
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