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 Gene 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 protein C12orf49 NM_024738 chr12:115646042-115646624 0 1 chromosome 12 open reading frame 49 C12orf49 NM_024738 chr12:115642036-115642761 0 1 chromosome 12 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 catenin, 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-amino acid 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 integrin, beta 5 ITGB5 NM_002213 chr3:125981166-125982064 0 1 integrin, beta 5 KIF13B NM_015254 chr8:29148303-29149459 0 1 kinesin 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 growth factor, 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 Cancer 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