Supplementary Table 1: Clinical and Pathological characteristics of tumor samples Serum Sample Tumor histology Age Gender DM HTN ESRD Creatinine Metastasis ID (gm/dl) Extends beyond Renal cell renal capsule, Tumor 1 carcinoma, clear cell 84 F N Y N 0.9 thrombus in renal type vein, Adenopathy Renal cell 3 carcinoma, clear cell 62 F N Y N 1.2 N type Renal cell 4 carcinoma, clear cell 57 F Y Y N 1.3 N type Renal cell 6 carcinoma, clear cell 63 F N N N 1.3 N type Renal cell 8 carcinoma, clear cell 58 M Y Y Y 1 N type Renal cell carcinoma, clear cell 10 69 M Y Y N 1 N type with focal papillary architecture Extension into Renal cell perinephric tissue, 11 carcinoma, clear cell 48 M Y Y N 1.3 renal sinus, renal type vein and lung Renal cell 12 carcinoma, clear cell 66 M N Y CKD 2.4 N type Renal cell 13 carcinoma, clear cell 54 F Y N N 0.9 Adenopathy+ type Renal cell carcinoma, clear cell Bilateral kidney 14 47 M Y Y Y 12.6 type multilocular lesions cystic variant Renal cell Extends into renal 19 carcinoma, clear cell 69 F N Y N 1 vein type Renal cell 21 carcinoma, clear cell 18 F N N N 1 N type Renal cell 22 carcinoma, clear cell 65 F N N Y 5.8 N type

HTN: Hypertension, ESRD: End stage renal disease, DM: Diabetes Mellitus, Supplementary Table 2: Aberrantly methylated and underexpressed loci with overlapping enhancer (H3K4me1) marks Name Refseq ID Chromosomal Location Promoter Intragenic Gene AGPAT3 NM_020132 chr21:44173228-44173889 0 1 1-acylglycerol-3-phosphate O-acyltransferase 3 ALDH4A1 NM_003748 chr1:19087954-19088127 0 1 aldehyde dehydrogenase 4 family, member A1 ARHGEF3 NM_019555 chr3:56756502-56756626 0 1 Rho guanine nucleotide exchange factor (GEF) 3 ARNT2 NM_014862 chr15:78494479-78494996 0 1 aryl-hydrocarbon receptor nuclear translocator 2 ARNT2 NM_014862 chr15:78573982-78574898 0 1 aryl-hydrocarbon receptor nuclear translocator 2 ATP6V0A4 NM_020632 chr7:138113827-138114236 0 1 ATPase, H+ transporting, lysosomal V0 subunit a4 BANP NM_017869 chr16:86595763-86596862 0 1 BTG3 associated nuclear C12orf49 NM_024738 chr12:115646042-115646624 0 1 12 open 49 C12orf49 NM_024738 chr12:115642036-115642761 0 1 open reading frame 49 CACNB4 NM_000726 chr2:152614969-152615444 0 1 calcium channel, voltage-dependent, beta 4 subunit CNNM2 NM_017649 chr10:104819168-104819290 0 1 cyclin M2 CNNM2 NM_017649 chr10:104790991-104792018 0 1 cyclin M2 CNNM2 NM_017649 chr10:104828109-104828622 0 1 cyclin M2 CTNNBIP1 NM_020248 chr1:9883307-9884482 0 1 , beta interacting protein 1 CYP24A1 NM_000782 chr20:52217893-52218110 0 1 cytochrome P450, family 24, subfamily A, polypeptide 1 DDC NM_000790 chr7:50566647-50567423 0 1 dopa decarboxylase (aromatic L- decarboxylase) EPN1 NM_013333 chr19:60888891-60889508 0 1 epsin 1 EPN1 NM_013333 chr19:60889903-60890539 0 1 epsin 1 EPN1 NM_013333 chr19:60890581-60891050 0 1 epsin 1 FHOD3 NM_025135 chr18:32215178-32215984 0 1 formin homology 2 domain containing 3 FHOD3 NM_025135 chr18:32538791-32539245 0 1 formin homology 2 domain containing 3 FHOD3 NM_025135 chr18:32134301-32134536 0 1 formin homology 2 domain containing 3 GMDS NM_001500 chr6:1568864-1569225 0 1 GDP-mannose 4,6-dehydratase GMDS NM_001500 chr6:1746328-1746930 0 1 GDP-mannose 4,6-dehydratase GMDS NM_001500 chr6:1663538-1663811 0 1 GDP-mannose 4,6-dehydratase GMDS NM_001500 chr6:1653712-1653952 0 1 GDP-mannose 4,6-dehydratase HSD11B2 NM_000196 chr16:66024649-66025060 0 1 hydroxysteroid (11-beta) dehydrogenase 2 HSD11B2 NM_000196 chr16:66028570-66029814 0 1 hydroxysteroid (11-beta) dehydrogenase 2 HSD11B2 NM_000196 chr16:66027123-66027242 0 1 hydroxysteroid (11-beta) dehydrogenase 2 HSD11B2 NM_000196 chr16:66028209-66028379 0 1 hydroxysteroid (11-beta) dehydrogenase 2 IQGAP2 NM_006633 chr5:75828704-75829645 0 1 IQ motif containing GTPase activating protein 2 ITGB5 NM_002213 chr3:126044913-126045276 0 1 , beta 5 ITGB5 NM_002213 chr3:125981166-125982064 0 1 integrin, beta 5 KIF13B NM_015254 chr8:29148303-29149459 0 1 family member 13B LETM1 NM_012318 chr4:1813924-1814512 0 1 leucine zipper-EF-hand containing transmembrane protein 1 LETM1 NM_012318 chr4:1793513-1793723 0 1 leucine zipper-EF-hand containing transmembrane protein 1 MAL NM_002371 chr2:95069524-95070748 0 1 mal, T-cell differentiation protein MAL NM_002371 chr2:95070749-95071008 0 1 mal, T-cell differentiation protein MAL NM_002371 chr2:95079186-95079377 0 1 mal, T-cell differentiation protein MAN1C1 NM_020379 chr1:25887729-25888154 0 1 mannosidase, alpha, class 1C, member 1 MAN1C1 NM_020379 chr1:25866389-25867076 0 1 mannosidase, alpha, class 1C, member 1 MPPED2 NM_001584 chr11:30505570-30506470 0 1 metallophosphoesterase domain containing 2 NISCH NM_007184 chr3:52462145-52462859 1 0 nischarin PCGF2 NM_007144 chr17:34144023-34144172 0 1 polycomb group ring finger 2 PLCG2 NM_002661 chr16:80442915-80444292 0 1 phospholipase C, gamma 2 (phosphatidylinositol-specific) PLEKHA6 NM_014935 chr1:202490710-202491435 0 1 pleckstrin homology domain containing, family A member 6 PLEKHA6 NM_014935 chr1:202557246-202558125 0 1 pleckstrin homology domain containing, family A member 6 PLEKHA6 NM_014935 chr1:202535289-202535653 0 1 pleckstrin homology domain containing, family A member 6 PLEKHA6 NM_014935 chr1:202499059-202499640 0 1 pleckstrin homology domain containing, family A member 6 PLEKHA6 NM_014935 chr1:202554265-202554691 0 1 pleckstrin homology domain containing, family A member 6 RALGPS1 NM_014636 chr9:128765901-128766442 0 1 Ral GEF with PH domain and SH3 binding motif 1 RALGPS1 NM_014636 chr9:128981567-128981870 0 1 Ral GEF with PH domain and SH3 binding motif 1 RALGPS1 NM_014636 chr9:128764778-128765900 0 1 Ral GEF with PH domain and SH3 binding motif 1 RXRA NM_002957 chr9:136468548-136469076 0 1 retinoid X receptor, alpha S100A2 NM_005978 chr1:151802759-151803151 0 1 S100 calcium binding protein A2 S100A2 NM_005978 chr1:151802759-151803151 1 0 S100 calcium binding protein A2 SELENBP1 NM_003944 chr1:149607800-149608122 0 1 selenium binding protein 1 SEMA3B NM_004636 chr3:50283452-50283534 0 1 semaphorin 3B SLC25A38 NM_017875 chr3:39401457-39402313 0 1 solute carrier family 25, member 38 SLC25A38 NM_017875 chr3:39401457-39402313 1 0 solute carrier family 25, member 38 SLC2A9 NM_020041 chr4:9540027-9540442 0 1 solute carrier family 2 (facilitated glucose transporter), member9 SMAD6 NM_005585 chr15:64827758-64828360 0 1 SMAD family member 6 SMAD6 NM_005585 chr15:64820486-64821212 0 1 SMAD family member 6 SMAD6 NM_005585 chr15:64804315-64804393 0 1 SMAD family member 6 SMAD6 NM_005585 chr15:64826825-64827332 0 1 SMAD family member 6 TACC2 NM_006997 chr10:123964741-123964996 0 1 transforming, acidic coiled-coil containing protein 2 TFCP2L1 NM_014553 chr2:121728700-121729880 0 1 transcription factor CP2-like 1 TFCP2L1 NM_014553 chr2:121744467-121744956 0 1 transcription factor CP2-like 1 TFCP2L1 NM_014553 chr2:121752377-121753466 0 1 transcription factor CP2-like 1 TFCP2L1 NM_014553 chr2:121717020-121717483 0 1 transcription factor CP2-like 1 TFCP2L1 NM_014553 chr2:121753467-121754391 0 1 transcription factor CP2-like 1 TFCP2L1 NM_014553 chr2:121716227-121716396 0 1 transcription factor CP2-like 1 TFCP2L1 NM_014553 chr2:121754663-121755146 0 1 transcription factor CP2-like 1 TFCP2L1 NM_014553 chr2:121746786-121747338 0 1 transcription factor CP2-like 1 TGFBR3 NM_003243 chr1:92027599-92027753 0 1 transforming , beta receptor III TMCO3 NM_017905 chr13:113246036-113246401 0 1 transmembrane and coiled-coil domains 3 TMCO3 NM_017905 chr13:113246726-113246914 0 1 transmembrane and coiled-coil domains 3 TMCO3 NM_017905 chr13:113246915-113247655 0 1 transmembrane and coiled-coil domains 3 TMCO3 NM_017905 chr13:113250736-113251115 0 1 transmembrane and coiled-coil domains 3 VAV2 NM_003371 chr9:135804920-135805577 0 1 vav 2 guanine nucleotide exchange factor VAV2 NM_003371 chr9:135728436-135729001 0 1 vav 2 guanine nucleotide exchange factor VAV2 NM_003371 chr9:135638784-135639447 0 1 vav 2 guanine nucleotide exchange factor VAV2 NM_003371 chr9:135804813-135804919 0 1 vav 2 guanine nucleotide exchange factor VAV2 NM_003371 chr9:135718971-135719481 0 1 vav 2 guanine nucleotide exchange factor VAV2 NM_003371 chr9:135798780-135798946 0 1 vav 2 guanine nucleotide exchange factor

Supplementary Table 3: Transcription factor binding sites enriched in differentially methylated regions in RCC.

Transcription factor Hits P Value

AP2alpha 26903 0 AhR 3690 1.352787E-316 Hairy 3208 2.67E-306 Sp-1 3302 2.68E-305 Pax-4 3042 3.22E-246 MAZ 2615 1.47E-194 Max 2777 3.65E-192 E2F 5394 3.43E-189 Pax-3 4054 3.69E-161 CREB 4405 2.00E-154 MyoD 1904 3.54E-149 E2A 3080 1.52E-144 VDR 3130 3.70E-138 E12 2218 4.49E-137 Arnt 1965 2.05E-131 USF 1876 3.28E-127 c-MycMax 1765 4.66E-110 E2F-1 2449 7.52E-109 Bsap 1536 1.31E-102 HIF-1 1226 1.53E-99 Supplementary Table 4: List of Gene and Pathways hypermethylated and underexpressed in RCC

Category P- Molecules Value Cellular 3.86E- AGTR1,ALDOA,ANGPT2,BID,CD9,CD97,CD99,CDH13,CDH4,CSF1R,CTBP1,DDR1,DIAPH2,DISC1,DKK3,DOCK Movement 16 4,DPYSL2,EGFR,ELMO1,ENG,ERBB3,FHL1,FLT1,FOXO3,FSCN1,GNA11,HOXA7,ICAM1,ICAM2,IGF2R,IL32,IQ GAP1,ITGAM,ITGB2,JAK2,KAL1,KDR,LAMB1,LAMC1,LIMS1,MAP3K14,MCM3,MET,MMP2,NUAK1,PALLD,PCSK 6,PDGFRB,RPS19,SCARB1,SDCBP,SLC2A1,SMAD7,SPARC,STAT1,TAGLN,TCIRG1,TGFA,THBD,THBS1,THBS 2,TIMP3,TLR2,TNFAIP8,TNFRSF1B,TP53,TPM1 (includes EG:22003),VEGFB,ZEB2 1.90E- ABCG1,AGTR1,AKAP13,ALDOA,ALOX5,AMFR,ANGPT2,ANP32A,BCL6,C18orf1,CAPG,CBFB,CD9,CD97,CD99, 14 CDH13,CDH4,CLDN7,COL15A1,COL1A2,COL6A3,CP,CSF1R,CTBP1,DDB2,DDR1,DIAPH2,DMD,DPYD,DPYSL2 ,EDNRA,EGFR,EIF4G3,ELMO1,ENG,ERBB3,ERF,F8,FBN1,FHL1,FLI1,FLT1,FOXO3,FSCN1,GNA11,GSPT1,HDA C9,HIP1,HLA-OXA4,ICAM1,ICAM2,IGF2R,IL32,IQGAP1,IRF2,ITGB2,JAK2, KDR,KIAA0101,LAMA4,LAMP3, LDB2,LSM7,LSR,MCM3,MELK,MET,MMP2,MN1,MSX1,MTR,MXI1,MYH11,NPC1,NPY1R,NUAK1,NVL,PALLD,PA PSS2,PAWR,PCSK6,PDCD6,PDE4A,PDGFRB,PDIA6,PFKP,PLIN3,PPM1D,PPP1R2,PRMT1,PSMB10,RAD50,RB 1,RBBP6,RBP1,RCC1,RPS19,RRAD,SCARB1,SEMA3C,SLC1A3,SLC2A1,SLC2A3,SLC6A3,SMAD7,SOCS5,SOR BS2,SPARC,STAT1,TAGLN,TBC1D4,TCF4,TGFA,THBD,THBS1,TIMP3,TLE3,TLR2,TP53,TPM1 (includes EG:22003),VEGFB,YWHAZ,ZEB2,ZNF148 Tissue 3.57E- AEBP1,AGTR1,ANGPT2,BPTF,CDH13,COL1A2,COL6A3,CSF1R,DISC1,DPYSL2,EDNRA,EGFR,ENG,ERBB3,FB Development 11 N1,FLI1,FLT1,IL32,JAK2,KALRN,KDR,LAMB1,LAMC1,MET,MMP2,MYH11,NPY1R,PAPSS2,PCSK5,PDGFRB,PL OD1,PRMT1,RAB11A,SPARC,STAT1,SVIL,THBS1,THBS2,TIE1,TIMP3,TLE1,TLE3,TP53,TPM1 (includes EG:22003),VEGFB

Reproductive 4.50E- ABCG1,AGTR1,ALDOA,ALOX5,ANGPT2,BCL6,C18orf1,CD97,CDH13,CDH4,COL15A1,COL6A3,CP,CSF1R,DDR System 10 1,DIAPH2,EDNRA,EGFR,ERBB3,FBN1,FHL1,FLT1,HDAC9,HOXA4,HYAL2,ICAM1,IGF2R,IQGAP1,ITGAM,KAL1, Disease KDR,KIAA0101,LAMA4,LDB2,MEF2A,MET,MMP2,MSX1,MYH11,PAPSS2,PAWR,PDGFRB,PHACTR2,PKD2 (includes EG:18764), RB1,RBBP6,RPS19,SEMA3C,SLC2A3,SLC6A3,SMAD7,SORBS2, STAT1,TAGLN,TCF4, THBS1, THBS2,TIMP3,TNFRSF1B,TP53,TPM1 (includes EG:22003),ZNF148 Cell Death 1.60E- ADRM1,AKAP13,ALOX5,BCL6,BID,CAMK2G,CD99,CSF1R,CTBP1,DKK3,EEF2,EGFR,ERBB3,FLI1,FLT1,FOXO3 09 ,HIP1,HOXA7,HSPB11,IFI16,IFI6,IGF2R,IL32,ITGAM,KDR,LIMS1,LOC100510692/NAIP,MEF2A,MELK,MET,MSX1 ,NFE2L2,NUAK1,PAWR,PCBP2,PDGFRB,PLAGL1,PPM1D,RB1,RBBP6,RPS19,SIVA1,SLC2A1,SMAD7,SMN1/S MN2,SPARC,STAT1,TCF4,TGFA,THBS1,TIMP3,TLR2,TNFAIP8,TNFRSF1B,TP53,TPM1 (includes EG:22003),TTF1,YWHAZ,ZFYVE16,ZNF148 Genetic 1.79E- ABCG1,ABLIM3,AEBP1,AGTR1,AKAP11,AKAP13,ALDOA,ALOX5,ALOX5AP,AMFR,ANGPT2,ANKRD6,ANP32A,A Disorder 09 OAH,ARHGAP25,AZIN1,BACH1,BCL6,BPTF,BTBD3,C18orf1,CAPG,CBFB,CD9,CDH13,CDH4,CHMP2B,CLN5,C OL15A1,COL1A2,COL6A3,COPE,CP,CPE,CSF1R,CTR9,CUL2,DCTN1,DDB2,DDR1,DIAPH2,DISC1,DKK3,DMD, DOCK4,DOPEY2,DPYD,DPYSL2,EDNRA,EEF2,EGFR,EIF4G3,ELMO1,ENG,ERBB3,F8,FAM13A,FBN1,FHL1,FLI 1,FLT1,FOXN3,FOXO3,FSCN1,GIT2,GNA11,GRK5,GYPC,GYS1,HDAC9,HIP1,HLA- E,HPCAL1,HYAL2,ICAM1,IFI16,IFI6,IGF2R,IQGAP1,IRF2,ITGAM,ITGB2,JAK2,KAL1,KALRN,KDR,KIAA0101,LAM A4,LAMB1,LAMP3,LDB2,LOC100510692/NAIP,LPCAT1,LPHN2,LRRFIP1,LY75,MAPRE2,MATR3,MCM3,MEF2A, MELK,MERTK,MET,MMP2,MN1,MSX1,MTR,MXI1,MYH11,MYO5A,NFE2L2,NPC1,OASL,OGDH,PABPC4,PABPN 1,PALLD,PAPSS2,PARP4,PAWR,PCBP2,PCSK5,PCSK6,PDCD6,PDE4A,PDGFRB,PER2,PFKP,PHACTR2,PHB2, PLAGL1,PLIN3,PLOD1,PPP1R2,PSMB10,RAB11A,RAPGEF4,RB1,RCBTB2,RCC1,RHOBTB3,RPL21,RPS19,RR AD,RYK,SCARB1,SDC3,SEC24D,SEMA3C,SFSWAP,SLC1A3,SLC2A1,SLC2A3,SLC6A3,SLCO2A1,SLCO2B1,S MN1/SMN2,SOCS5,SORBS2,SPARC,SREBF1,STAT1,SVIL,SYNE2,TAGLN,TBC1D4,TBCE,TCF4,TCIRG1,TGFA, THBD,THBS1,THBS2,TIMP3,TLE1,TLE3,TLR2,TNFRSF1B,TP53,TPM1 (includes EG:22003),TUBGCP3,USP8,YWHAZ,ZEB2,ZNF148 Cellular Growth 2.20E- AKAP13,ANGPT2,ANKRD6,ANP32A,BCL6,BID,CD9,CDH13,CDH4,CSF1R,CTBP1,CUL2,DISC1,EAPP,EGFR,EN and 09 G,ERBB3,ERF,FHL1,FLI1,FLT1,FOXO3,FSCN1,GNA11,HOXA7,ICAM1,IFI16,IGF2R,IL32,IRF2,ITGB2,JAK2,KDR, Proliferation KIAA0101,LAMB1,LAMC1,LAMP3,LY75,MAPRE2,MET,MMP2,MXI1,NACA,PAWR,PCSK6,PDCD6,PDGFRB,PFK P,PPM1D,RB1,RBP1,RPS19,SLC2A1,SMAD7,SPARC,STAT1,TCF4,TCIRG1,TGFA,THBS1,THBS2,TIMP3,TLR2, TNFAIP8,TNFRSF1B,TP53,USP8,VEGFB Gene 2.57E- AKAP13,ANGPT2,ANP32A,AP2B1,BACH1,BCL6,BPTF,CBFB,CD9,CEP350,CTBP1,DDB2,DVL3,EAPP,EEF1D,E Expression 09 GFR,ENG,ERBB3,ERF,FLI1,FOXO3,HDAC9,HIP1,HOXA7,HYAL2,IFI16,IGF2R,IQGAP1,IRF2,JAK2,KDR,LRRFIP 1,MAP3K14,MEF2A,MET,MN1,MXI1,MYH11,NFE2L2,NFE2L3,PABPN1,PAWR,PLAGL1,RB1,RLF,SMAD7,SREBF 1,STAT1,TAGLN,TCF4,TGFA,TLR2,TNFRSF1B,TP53,TRAF5,TTF1,VEZF1,ZNF148

Cell Death 2.79E- ADRM1,AKAP13,ALOX5,BCL6,BID,CAMK2G,CD99,CSF1R,CTBP1,DKK3,EEF2,EGFR,ERBB3,FLI1,FLT1,FOXO3 09 ,HIP1,HOXA7,HSPB11,IFI16,IFI6,IGF2R,IL32,ITGAM,KDR,LIMS1,LOC100510692/NAIP,MEF2A,MELK,MET,MSX1 ,NFE2L2,NUAK1,PAWR,PCBP2,PDGFRB,PLAGL1,PPM1D,RB1,RBBP6,RPS19,SIVA1,SLC2A1,SMAD7,SMN1/S MN2,SPARC,STAT1,TCF4,TGFA,THBS1,TIMP3,TLR2,TNFAIP8,TNFRSF1B,TP53,TTF1,ZFYVE16,ZNF148 Gene 6.88E- AEBP1,AKAP13,ANGPT2,ANP32A,AP2B1,BACH1,BCL6,BPTF,CBFB,CD9,CEP350,CTBP1,DDB2,DKK3,DVL3,EA Expression 09 PP,EEF1D,EGFR,ENG,ERBB3,ERF,FLI1,FOXN3,FOXO3,HDAC9,HIP1,HOXA7,HYAL2,IFI16,IGF2R,IQGAP1,IRF2 ,JAK2,KDR,LRRFIP1,MAP3K14,MATR3,MEF2A,MET,MN1,MSX1,MXI1,MYH11,NFE2L2,NFE2L3,PABPN1,PAWR, PHB2,PLAGL1,PPM1D,PSMB10,RB1,RBBP6,RLF,SMAD7,SREBF1,STAT1,TAGLN,TCF4,TGFA,TLE1,TLR2,TNF RSF1B,TP53,TRAF5,VEZF1,YWHAZ,ZFYVE16,ZNF148

Supplementary Table 5: deleted in RCC No. of samples Genomic Location Gene Symbol with deletion chr3:48105751-48106112 MAP4 6 chr3:47596896-47597490 CSPG5 5 chr3:47798824-47799106 SMARCC1 5 chr3:48204884-48205283 CDC25A 5 chr3:57558640-57558958 ARF4 5 chrX:23635979-23636287 ACOT9 5 chrX:54057408-54058245 PHF8 5 chrX:54226311-54226571 FAM120C 5 chr3:47820158-47820685 DHX30 5 chrX:23709796-23710791 SAT1 5 chr13:19325852-19326442 ZMYM5 5 chr16:57326261-57326716 GOT2 4 chr3:47530874-47531694 C3orf75 4 chr3:48769832-48770416 PRKAR2A 4 chr3:48911410-48912154 SLC25A20 4 chr3:49352895-49353513 USP4 4 chr3:49425998-49426693 RHOA 4 chr3:51510032-51510526 VPRBP 4 chrX:24575803-24576745 PCYT1B 4 chr3:47840657-47841438 DHX30 4 chr3:48929876-48930334 ARIH2 4 chr3:49001455-49002120 P4HTM 4 chr3:49481778-49482152 DAG1 4 chr3:57235996-57236561 APPL1 4 chrX:24459393-24460024 PDK3 4 chrX:24620701-24621577 POLA1 4 chrX:118585340-118586300 CXorf56 4 chrX:118612254-118613090 NKRF 4 chrX:118711213-118711596 GLYR1 /// SEPT6 4 chrX:118872275-118873010 UPF3B 4 chrX:117992205-117992536 LONRF3 4 chrX:118253329-118253655 PGRMC1 4 chrX:118887219-118887782 NDUFA1 4 chr13:19256664-19257155 PSPC1 4 chr14:34661989-34662606 PPP2R3C 3 chr3:12682333-12683294 RAF1 3 chr3:12777482-12777906 TMEM40 3 chr3:24512563-24513190 THRB 3 chr3:25681477-25681741 TOP2B 3 chr3:28365799-28366073 AZI2 3 chr3:31921468-31921937 OSBPL10 3 chr3:32588056-32588819 DYNC1LI1 3 chr3:33114767-33115557 GLB1 3 chr3:33236881-33237212 SUSD5 3 chr3:33458408-33459044 UBP1 3 chr3:37009703-37010176 EPM2AIP1 3 chr3:37167359-37168184 LRRFIP2 3 chr3:47493613-47493920 SCAP 3 chr3:47530448-47530739 C3orf75 3 chr3:48206459-48206987 CDC25A 3 chr3:48698799-48699585 NCKIPSD 3 chr3:48707733-48708013 IP6K2 3 chr3:49032502-49033236 DALRD3 3 chr3:49041557-49042103 IMPDH2 3 chr3:52715914-52716317 GLT8D1 3 chr14:34521033-34521570 SRP54 3 chr14:34521571-34521886 SRP54 3 chr14:34660258-34660587 KIAA0391 3 chr14:57781785-57782309 PSMA3 3 chr3:10157606-10158215 VHL 3 chr3:10264472-10264879 TATDN2 3 chr3:11313999-11314576 ATG7 3 chr3:12570817-12571703 MKRN2 3 chr3:12812224-12812992 CAND2 3 chr3:23822356-23822616 UBE2E1 3 chr3:23932971-23933331 RPL15 3 chr3:23959403-23959819 NR1D2 3 chr3:25442538-25443051 RARB 3 chr3:25442538-25443051 LOC100130354 3 chr3:32207641-32208436 RPSA 3 chr3:33128415-33129253 CRTAP 3 chr3:33293233-33293822 FBXL2 3 chr3:33815094-33815544 PDCD6IP 3 chr3:37009703-37010176 MLH1 3 chr3:37258111-37258668 GOLGA4 3 chr3:37291635-37292068 TCEA1 3 chr3:48237956-48238653 CAMP 3 chr3:48257520-48257919 ZNF589 3 chr3:49019574-49019955 WDR6 3 chr3:49032502-49033236 NDUFAF3 3 chr3:49544059-49544316 DAG1 3 chr3:49565839-49566121 BSN 3 chr3:52694952-52695373 GNL3 3 chr3:52712404-52713235 SPCS1 3 chr6:150081502-150081790 LATS1 3 chr6:150111065-150111359 PCMT1 3 chrX:70420215-70420572 NONO 3 chrX:70501708-70502339 TAF1 3 chr1:32889726-32890336 RBBP4 3 chr13:19255717-19256663 PSPC1 3 chr1:459884-460930 RPL23AP53 3 chr1:798390-798722 TUBB4Q 3 chr1:938739-939095 ISG15 3 chr1:945790-945897 AGRN 3 Supplementary Table 6: Genes amplified in RCC

No. of samples Genomic Location Gene Symbol with amplification chr17:31689-32160 DOC2B 7 chr12:117736-118156 IQSEC3 7 chr17:78604442-78605350 B3GNTL1 6 chr16:88613617-88613890 DBNDD1 5 chr16:88623520-88623825 C16orf3 5 chr22:49363667-49364027 CHKB-CPT1B /// CPT1B 5 chr22:49413803-49414796 ARSA 5 chr7:526454-526751 PDGFA 5 chr22:49384495-49384829 MAPK8IP2 5 chr7:143691994-143692418 ARHGEF5 5 chr9:140189605-140189915 TUBBP5 5 chr19:63767203-63768191 MZF1 4 chr19:63778280-63778540 MGC2752 4 chr16:44410-44808 POLR3K 4 chr16:62755-63352 RHBDF1 4 chr16:78499-79311 NPRL3 4 chr16:732281-733236 NARFL 4 chr16:790743-791009 GNG13 4 chr16:861702-862170 LMF1 4 chr16:1215896-1216179 TPSG1 4 chr17:78391131-78391724 ZNF750 4 chr19:63758464-63759172 CHMP2A 4 chr20:62058221-62058606 UCKL1 4 chr20:62070427-62070896 ZNF512B 4 chr20:62151848-62152287 SOX18 4 chr20:62183204-62183613 RGS19 4 chr20:62208754-62209323 NPBWR2 4 chr16:40683-41349 SNRNP25 4 chr16:68945-69586 MPG 4 chr16:516329-516756 SOLH 4 chr16:557898-558276 PIGQ 4 chr16:663040-663354 RHOT2 4 chr16:664086-664368 RHBDL1 4 chr16:668594-668956 STUB1 4 chr16:703498-703938 METRN 4 chr16:751850-752359 MSLN 4 chr16:1141921-1142428 CACNA1H 4 chr18:108470-109338 ROCK1 4 chr20:62081937-62082659 PRPF6 4 chr20:62163822-62164735 TCEA2 4 chr20:62191545-62192362 OPRL1 4 chr20:62264199-62264510 MYT1 4 chr20:62307685-62308124 PCMTD2 4 chr5:134763023-134763338 H2AFY 4 chrX:152382986-152383736 HAUS7 4 chrX:152490326-152491085 ATP2B3 4 chrX:152709671-152710004 IDH3G 4 chrX:152805403-152805715 L1CAM 4 chrX:152845141-152845522 ARHGAP4 4 chrX:152854083-152854497 NAA10 4 chrX:152864167-152864801 RENBP 4 chrX:152891770-152892161 HCFC1 4 chrX:153240651-153240986 FLNA 4 chrX:153292481-153292990 DNASE1L1 4 chrX:153362123-153362738 LAGE3 4 chrX:153368369-153368700 UBL4A 4 chrX:153373530-153373898 SLC10A3 4 chrX:153399313-153399818 FAM3A 4 chr17:78438508-78439343 TBCD 4 chr19:63659090-63659536 ZNF324B /// ZNF584 4 chr19:63747030-63747540 TRIM28 4 chrX:67965309-67965657 EFNB1 4 chrX:152412468-152412830 BGN 4 chrX:152559332-152560086 DUSP9 4 chrX:152605520-152605970 SLC6A8 4 chrX:152680860-152681410 PLXNB3 4 chrX:152698603-152699368 SRPK3 4 chrX:152710473-152711334 SSR4 4 chrX:152821566-152822311 AVPR2 4 chrX:152890107-152890498 TMEM187 4 chrX:153098932-153099577 OPN1LW /// OPN1MW /// OPN1MW2 4 chrX:153259345-153259620 EMD 4 chrX:153278347-153278758 RPL10 4 chrX:153292481-153292990 TAZ 4 chrX:153309815-153310123 ATP6AP1 4 chrX:153315859-153316850 GDI1 4 chrX:153323342-153323762 FAM50A 4 chrX:153422876-153423488 IKBKG 4 chr12:192393-192774 SLC6A12 4 chrY:10186920-10187434 TTTY2 /// TTTY2B 3 chrX:3829785-3830486 LOC286434 3 chr8:146248265-146248663 C8orf33 3 chr13:114088369-114089087 UPF3A 3 chr14:104706697-104707244 JAG2 3 chr16:1317182-1317446 UBE2I 3 chr16:1340309-1340589 C16orf42 3 chr16:1371546-1371800 UNKL 3 chr16:87245962-87246318 CYBA 3 chr16:87257910-87258779 MVD 3 chr16:87330034-87330761 FAM38A 3 chr16:87406403-87406733 APRT 3 chr16:87450852-87451117 GALNS 3 chr19:60864529-60865070 U2AF2 3 chr22:49042857-49043593 MAPK12 3 chr22:49051519-49051789 MAPK11 3 chr22:49060941-49061236 PLXNB2 3 chr5:578258-578551 SLC9A3 3 chr5:747884-748230 TPPP 3 chrX:2892954-2893466 ARSE 3 chrX:3642037-3642335 PRKX /// PRKY 3 chrX:3642037-3642335 PRKX 3 chrX:3747434-3747839 LOC286434 /// LOC389906 /// LOC729162 3 chrX:39807251-39807510 BCOR 3 chr11:1365799-1366510 BRSK2 3 chr16:1066355-1067210 SSTR5 3 chr16:1216287-1216638 TPSAB1 3 chr16:1322189-1322482 BAIAP3 3 chr16:32786614-32786912 BCAP31 3 chr19:60877666-60878000 EPN1 3 chr21:46797535-46797927 DIP2A 3 chr21:46878983-46879880 PRMT2 3 chr22:48964489-48964789 TRABD 3 chr5:323631-323918 PDCD6 3 chr5:505355-506133 EXOC3 3 chr5:131357678-131358657 ACSL6 3 chr5:131439471-131439928 CSF2 3 chr5:131590222-131590598 P4HA2 3 chr5:131635868-131636380 PDLIM4 3 chr5:132101068-132101345 KIF3A 3 chr5:134899786-134900537 NEUROG1 3 chr5:134942107-134942373 CXCL14 3 chr7:149097203-149097993 ZNF467 3 chr7:158630385-158630674 VIPR2 3 chrX:152135709-152136453 MAGEA1 3 chrX:153176634-153177090 TEX28 3 chr10:135055827-135056201 MTG1 3 chr10:135188952-135189336 CYP2E1 3 chr16:87396253-87396543 CDT1 3 chr16:87449002-87449369 TRAPPC2L 3 chr19:63589251-63589605 RPS5 3 chr3:128233547-128234167 PLXNA1 3 chr5:131422703-131423005 IL3 3 chr5:131656950-131657206 SLC22A4 3 chr5:131733309-131733667 SLC22A5 3 chr5:131919267-131919572 RAD50 3 chr5:132035578-132036093 IL4 3 chrX:68640833-68641108 FAM155B 3 chrX:68750930-68751330 EDA 3 chrX:151835071-151835419 ZNF185 3 chrX:151975837-151976119 PNMA3 3 chrX:153175144-153175430 TKTL1 3 chr1:247098439-247098747 ZNF672 3 chr13:113917407-113918262 RASA3 3 chr13:114016403-114017107 CDC16 3 chrY:13524995-13525399 DDX3Y 3 chrY:14323108-14323703 TMSB4Y 3 chrY:18755195-18755721 XKRY /// XKRY2 3 chrY:18946061-18946402 NCRNA00230A 3 chrY:19614280-19615040 CD24 3 chrY:20366471-20367443 KDM5D 3 chrY:21146030-21146432 EIF1AY 3 RBMY1A1 /// RBMY1B /// RBMY1D /// RBMY1E /// RBMY1F /// chrY:22103925-22104599 RBMY1J 3 chrY:22864444-22865415 RBMY2FP 3 chrY:22994281-22994733 TTTY2 3 chrY:23774755-23775025 DAZ1 /// DAZ2 /// DAZ3 /// DAZ4 3 chrY:26037316-26038236 CSPG4PY1 /// CSPG4PY2 3