As was previously described, gene expression profiles of the 70 CCRCCs (performed on cdna

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1 RSNA, /radiol Appendix E1 Gene Expression Profiling Training Set As was previously described, gene expression profiles of the 70 CCRCCs (performed on cdna microarrays containing over 40,000 cdna clones and representing 27,290 unique UniGene clusters) were accessed from the Gene Expression Omnibus (GSE3538) (1). To filter the expression data to only those genes that were most variably expressed and well measured, we used the same filtering criteria as Zhao et al (1); array elements that varied at least two-fold from the median on at least five microarrays were selected for subsequent analysis (5332 cdna elements representing 4825 unique genes). Within these 5332 cdna elements, transcripts that were identified as part of the previously determined CCRCC prognostic gene expression signature were selected (217 transcripts representing 139 genes [Table E1]). Hierarchical clustering of the expression profiles are shown in Figure E1. Kaplan-Meier survival analysis was performed between the low and high prognostic patient groups, confirming that the 259 prognostic gene signatures remained a significant predictor of survival in our population (P =.0031). Validation Set Gene expression profiles of the 70 CCRCCs was performed on Illumina Human HT-12 v4 Expression BeadChip arrays (Illumina, San Diego, Calif), which contained 47,231 probes. Page 1 of 22

2 Quantile normalization was performed with the lumi R package (2). The expression arrays were filtered on the basis of the set of SPC transcripts that mapped to the Illumina probes. References 1. Zhao H, Ljungberg B, Grankvist K, Rasmuson T, Tibshirani R, Brooks JD. Gene expression profiling predicts survival in conventional renal cell carcinoma. PLoS Med 2006;3(1):e Du P, Kibbe WA, Lin SM. lumi: a pipeline for processing Illumina microarray. Bioinformatics 2008;24(13): Page 2 of 22

3 Table E1. Annotation of SPC Transcripts UniGene ID Gene Description Hs Myelin protein zero-like 2::myelin protein zero-like 2 Hs AA IMAGE: MPZL Hs Tubulin tyrosine ligase-like family, member 7::tubulin tyrosine ligase-like family, member 7 Hs H29858::H29951 IMAGE: TTLL Hs Rho-related BTB domain containing 1::Rho-related BTB domain containing 1 Hs AA182796::AA IMAGE: RHOBTB Hs Discoidin, CUB and LCCL domain containing 2::discoidin, CUB and LCCL domain containing 2 Hs H99544::H99543 IMAGE: DCBLD Hs Guanine nucleotide binding protein (G protein), gamma 11::guanine nucleotide binding protein (G protein), gamma 11 Hs AA IMAGE: GNG Hs Palmdelphin::palmdelphin Hs AA418728::AA IMAGE: PALMD Hs Discoidin, CUB and LCCL domain containing 2::discoidin, CUB and LCCL domain containing 2 Hs AI IMAGE: DCBLD Hs Interferon induced transmembrane protein 1 (9 27)::interferon induced transmembrane protein 1 (9 27) Hs AA419251::AA IMAGE: IFITM Hs CDNA clone IMAGE: Hs AA IMAGE: Hs KIAA1147::KIAA1147 Hs AA029331::AA IMAGE: KIAA Hs Ankyrin 3, node of Ranvier (ankyrin G)::ankyrin 3, node of Ranvier (ankyrin G)::Transcribed locus Hs ::Hs AA021558::AA IMAGE: ANK Page 3 of 22

4 Hs Transcribed locus, strongly similar to NP_ regulator of G-protein signaling 5 [Homo sapiens] Hs AA IMAGE: Hs RAS-like, estrogen-regulated, growth inhibitor::ras-like, estrogen-regulated, growth inhibitor Hs AA131239::AA IMAGE: RERG Hs.7946 Mitochondrial tumor suppressor 1::mitochondrial tumor suppressor 1 Hs AA IMAGE: MTUS Hs Lymphoid-restricted membrane protein::lymphoid-restricted membrane protein Hs AA457051::AA IMAGE: LRMP Hs Nonmetastatic cells 1, protein (NM23A) expressed in::nonmetastatic cells 1, protein (NM23A) expressed in Hs AA496628::AA IMAGE: NME Hs Integrin, alpha 2 (CD49B, alpha 2 subunit of VLA-2 receptor)::integrin, alpha 2 (CD49B, alpha 2 subunit of VLA-2 receptor) Hs AA069027::AA IMAGE: ITGA Hs Zinc finger protein 189::zinc finger protein 189 Hs AA256471::AA IMAGE: ZNF Hs Vav 3 guanine nucleotide exchange factor::vav 3 guanine nucleotide exchange factor Hs W91879::W91952 IMAGE: VAV Hs Acyl-CoA synthetase medium-chain family member 2A::acyl-CoA synthetase medium-chain family member 2B Hs AA IMAGE: ACSM2B Hs Natriuretic peptide receptor C/guanylate cyclase C (atrionatriuretic peptide receptor C)::natriuretic peptide receptor C/guanylate cyclase C (atrionatriuretic peptide receptor C) Hs AI668687::N92291::AI734266::W24469 IMAGE: NPR Hs Transcribed locus Hs T68445::T68510 IMAGE: Hs Midline 1 (Opitz/BBB syndrome)::midline 1 (Opitz/BBB syndrome) Hs AA IMAGE: MID Hs Sprouty homolog 1, antagonist of FGF signaling (Drosophila)::sprouty homolog 1, antagonist of FGF signaling (Drosophila)::Transcribed locus Hs ::Hs AA055440::AA IMAGE: SPRY Page 4 of 22

5 Hs Transcribed locus::gm2 ganglioside activator::gm2 ganglioside activator Hs ::Hs AA983633::AI733175::AI IMAGE: GM2A Hs GNAS complex locus::gnas complex locus::transcribed locus Hs ::Hs AA285128::AA IMAGE: GNAS Hs Glutathione S-transferase A2::glutathione S-transferase A2 Hs T73468::T73535 IMAGE:82710 GSTA Hs Chromosome 5 open reading frame 23::chromosome 5 open reading frame 23 Hs N90806::W19519 IMAGE: C5orf Hs Glutathione S-transferase A2::glutathione S-transferase A2::Transcribed locus Hs.94107::Hs N59772::N78234 IMAGE: GSTA Hs Serine peptidase inhibitor, Kunitz type, 2::serine peptidase inhibitor, Kunitz type, 2 Hs AA031287::AA IMAGE: SPINT Hs CD52 molecule::cd52 molecule Hs AA435559::AA IMAGE: CD Hs Influenza virus NS1A binding protein::influenza virus NS1A binding protein Hs AA487115::AA IMAGE: IVNS1ABP Hs Lysyl oxidase::lysyl oxidase Hs AA452916::AA IMAGE: LOX Hs BCL2/adenovirus E1B 19kDa interacting protein 3-like::BCL2/adenovirus E1B 19kDa interacting protein 3-like Hs AA025112::AA IMAGE: BNIP3 L Hs Cytochrome P450, family 4, subfamily V, polypeptide 2::kallikrein B, plasma (Fletcher factor) 1 Hs AA450041::AA IMAGE: KLKB Hs GNAS complex locus::gnas complex locus Hs W88587 IMAGE: GNAS 1186 Hs Lysyl oxidase::lysyl oxidase::transcribed locus Hs ::Hs H80737::H80736 IMAGE: LOX Page 5 of 22

6 Hs Discoidin, CUB and LCCL domain containing 2::discoidin, CUB and LCCL domain containing 2 Hs AA457544::AA IMAGE: DCBLD Hs EH domain binding protein 1::EH domain binding protein 1 Hs AA IMAGE: EHBP Hs Golgi-localized protein::golgi-localized protein Hs T61269::T61321 IMAGE:77911 GOLSYN Hs Dimethylarginine dimethylaminohydrolase 1::dimethylarginine dimethylaminohydrolase 1 Hs AA478470::AA IMAGE: DDAH Hs Lysyl oxidase::lysyl oxidase::transcribed locus Hs ::Hs H99075::N26939 IMAGE: LOX Hs Tissue factor pathway inhibitor (lipoprotein-associated coagulation inhibitor)::tissue factor pathway inhibitor (lipoprotein-associated coagulation inhibitor) Hs AI IMAGE: TFPI Hs SH3 domain binding glutamic acid-rich protein like 2::SH3 domain binding glutamic acid-rich protein like 2 Hs W69271::W69558 IMAGE: SH3BGRL Hs Glutathione S-transferase A4::glutathione S-transferase A4 Hs N47484::N47483 IMAGE: GSTA Hs Major histocompatibility complex, class II, DR beta 3::major histocompatibility complex, class II, DR beta 1 Hs H52245::H52342 IMAGE: HLA-DRB Hs Endothelin receptor type B::endothelin receptor type B Hs N29914::N42964 IMAGE: EDNRB Hs Cadherin 1, type 1, E-cadherin (epithelial)::cadherin 1, type 1, E-cadherin (epithelial) Hs W86859 IMAGE: CDH Hs.8364 Pyruvate dehydrogenase kinase, isozyme 4::pyruvate dehydrogenase kinase, isozyme 4 Hs AA IMAGE: PDK Hs Egl nine homolog 3 (C. elegans)::egl nine homolog 3 (C. elegans) Hs AA IMAGE: EGLN Hs Leukemia inhibitory factor receptor alpha::leukemia inhibitory factor receptor alpha::transcribed locus Hs ::Hs H10192::H10240 IMAGE:46694 LIFR Page 6 of 22

7 Hs Elongation protein 3 homolog (S. cerevisiae)::elongation protein 3 homolog (S. cerevisiae) Hs AA482031::AA IMAGE: ELP Hs Interferon induced transmembrane protein 1 (9 27)::interferon induced transmembrane protein 1 (9 27) Hs AA IMAGE: IFITM Hs Poliovirus receptor-related 3::poliovirus receptor-related 3 Hs AA IMAGE: PVRL Hs Leukemia inhibitory factor receptor alpha::leukemia inhibitory factor receptor alpha::serine hydroxymethyltransferase 2 (mitochondrial)::serine hydroxymethyltransferase 2 (mitochondrial) Hs ::Hs ::6472 N67017::W04138 IMAGE: LIFR::SHMT Hs ST8 alpha-n-acetyl-neuraminide alpha-2,8-sialyltransferase 4::ST8 alpha-n-acetyl-neuraminide alpha-2,8-sialyltransferase 4 Hs AA IMAGE: ST8SIA Hs Aldehyde dehydrogenase 6 family, member A1::aldehyde dehydrogenase 6 family, member A1 Hs AA196287::AA IMAGE: ALDH6A Hs Transmembrane and tetratricopeptide repeat containing 1::transmembrane and tetratricopeptide repeat containing 1 Hs T60061 IMAGE:81316 TMTC Hs.5025 Nebulette::nebulette Hs N77806::W16723 IMAGE: NEBL Hs Sortilin-related receptor, L (DLR class) A repeats-containing::sortilin-related receptor, L (DLR class) A repeats-containing Hs T51538::T51689 IMAGE:72391 SORL Hs Integrin, alpha 6::integrin, alpha 6 Hs H07142::H06635 IMAGE:44814 ITGA Hs L1 cell adhesion molecule::l1 cell adhesion molecule Hs AI IMAGE: L1CAM Hs Alpha-2-macroglobulin::alpha-2-macroglobulin Hs ::AA IMAGE: A2M Hs Cadherin 1, type 1, E-cadherin (epithelial)::cadherin 1, type 1, E-cadherin (epithelial) Hs T62868::T62718 IMAGE:79598 CDH Hs Growth arrest-specific 2 like 3::growth arrest-specific 2 like 3 Hs N20305::N27574 IMAGE: GAS2 L Page 7 of 22

8 Hs BCL2/adenovirus E1B 19kDa interacting protein 3-like::BCL2/adenovirus E1B 19kDa interacting protein 3-like Hs AA IMAGE: BNIP3 L Hs Discoidin, CUB and LCCL domain containing 2::discoidin, CUB and LCCL domain containing 2 Hs N21309::N31244 IMAGE: DCBLD Hs Elongation protein 3 homolog (S. cerevisiae)::elongation protein 3 homolog (S. cerevisiae) Hs AA IMAGE: ELP Hs Vascular cell adhesion molecule 1::vascular cell adhesion molecule 1 Hs H16591::H16637 IMAGE:49164 VCAM Hs RAB11 family interacting protein 3 (class II)::RAB11 family interacting protein 3 (class II) Hs R38361::T77413 IMAGE:23794 RAB11FIP Hs Actin binding LIM protein 1::actin binding LIM protein 1 Hs AA IMAGE: ABLIM Hs Guanylate binding protein 3::guanylate binding protein 1, interferon-inducible, 67kDa Hs AA486850::AA IMAGE: GBP Hs chromosome 5 open reading frame 13::Chromosome 5 open reading frame 13 Hs H60560::H60254 IMAGE: C5orf Hs B-cell CLL/lymphoma 2::B-cell CLL/lymphoma 2 Hs W63749::W61100 IMAGE: BCL Hs Serine peptidase inhibitor, Kunitz type, 2::serine peptidase inhibitor, Kunitz type, 2 Hs AA458849::AA IMAGE: SPINT Hs myosin VB::Acetyl-Coenzyme A acyltransferase 2 Hs AA219282::AA IMAGE: MYO5B Hs Transcription factor AP-2 gamma (activating enhancer binding protein 2 gamma)::transcription factor AP-2 gamma (activating enhancer binding protein 2 gamma)::transcribed locus Hs ::Hs AA394236::AA IMAGE: TFAP2C Hs MOCO sulphurase C-terminal domain containing 2::MOCO sulphurase C-terminal domain containing 2::Transcribed locus Hs ::Hs T63490::T63565 IMAGE:81449 MOSC Page 8 of 22

9 Hs Caldesmon 1::caldesmon 1 Hs AA447737::AA IMAGE: CALD Hs Netrin 4::netrin 4 Hs R76614::R76613 IMAGE: NTN Hs CTP synthase::ctp synthase Hs W44416::W45678 IMAGE: CTPS Hs.8379 Transcribed locus Hs.8379 T41071::T40203 IMAGE: Hs Ral guanine nucleotide dissociation stimulator-like 1::ral guanine nucleotide dissociation stimulator-like 1::actin related protein 2/3 complex, subunit 5, 16kDa::Actin related protein 2/3 complex, subunit 5, 16kDa Hs ::Hs ::10092 AA169173::AA IMAGE: RGL1::ARPC Hs Family with sequence similarity 131, member C::family with sequence similarity 131, member C Hs AA IMAGE: FAM131C Hs Tissue factor pathway inhibitor (lipoprotein-associated coagulation inhibitor)::tissue factor pathway inhibitor (lipoprotein-associated coagulation inhibitor) Hs H91294::H91389 IMAGE: TFPI Hs Ectonucleotide pyrophosphatase/phosphodiesterase 3::ectonucleotide pyrophosphatase/phosphodiesterase 3 Hs AA IMAGE: ENPP Hs POU class 5 homeobox 1::POU class 5 homeobox 1 Hs AA IMAGE: POU5F Hs Glutathione S-transferase A4::glutathione S-transferase A4 Hs AA152347::AA IMAGE: GSTA Hs Glypican 6::glypican 6 Hs AA456147::AA IMAGE: GPC Hs Endothelial cell-specific molecule 1::endothelial cell-specific molecule 1 Hs W46577::W46667 IMAGE: ESM Hs Angiogenin, ribonuclease, RNase A family, 5::angiogenin, ribonuclease, RNase A family, 5 Hs AA IMAGE: ANG Hs Aldehyde dehydrogenase 6 family, member A1::aldehyde dehydrogenase 6 family, member A1 Hs N62179::N77107 IMAGE: ALDH6A Page 9 of 22

10 Hs Ankyrin 3, node of Ranvier (ankyrin G)::ankyrin 3, node of Ranvier (ankyrin G) Hs AA IMAGE: ANK Hs Influenza virus NS1A binding protein::influenza virus NS1A binding protein Hs AI IMAGE: IVNS1ABP Hs Family with sequence similarity 13, member A1::family with sequence similarity 13, member A1 Hs N51424 IMAGE: FAM13A Hs Family with sequence similarity 84, member B::family with sequence similarity 84, member B Hs AI IMAGE: FAM84B Hs Coagulation factor II (thrombin) receptor-like 1::coagulation factor II (thrombin) receptor-like 1::Transcribed locus Hs ::Hs AA454652::AA IMAGE: F2RL Hs Aldehyde dehydrogenase 6 family, member A1::aldehyde dehydrogenase 6 family, member A1 Hs AI IMAGE: ALDH6A Hs Sortilin-related receptor, L (DLR class) A repeats-containing::sortilin-related receptor, L (DLR class) A repeats-containing Hs AI IMAGE: SORL Hs KIAA0746 protein::kiaa0746 protein Hs AA IMAGE: KIAA Hs CDNA FLJ13937 fis, clone Y79AA Hs R53446::R53445 IMAGE: Hs Interferon induced transmembrane protein 1 (9 27)::interferon induced transmembrane protein 1 (9 27) Hs AA058323::AA IMAGE: IFITM Hs UDP glucuronosyltransferase 2 family, polypeptide B4::UDP glucuronosyltransferase 2 family, polypeptide B4 Hs N53031::N73214 IMAGE: UGT2B Hs.3281 Neuronal pentraxin II::neuronal pentraxin II Hs AA IMAGE: NPTX Hs Transforming, acidic coiled-coil containing protein 1::transforming, acidic coiled-coil containing protein 1 Hs H47327::H47413 IMAGE: TACC Page 10 of 22

11 Hs Coagulation factor II (thrombin) receptor-like 1::coagulation factor II (thrombin) receptor-like 1 Hs AI IMAGE: F2RL Hs Solute carrier family 5 (sodium/glucose cotransporter), member 12::solute carrier family 5 (sodium/glucose cotransporter), member 12 Hs AA994816::AI IMAGE: SLC5A Hs.66 Interleukin 1 receptor-like 1::interleukin 1 receptor-like 1 Hs AA128153::AA IMAGE: IL1RL Hs Natriuretic peptide receptor C/guanylate cyclase C (atrionatriuretic peptide receptor C)::natriuretic peptide receptor C/guanylate cyclase C (atrionatriuretic peptide receptor C) Hs AI IMAGE: NPR Hs Leukemia inhibitory factor receptor alpha::leukemia inhibitory factor receptor alpha Hs AA131466::AA IMAGE: LIFR Hs Transmembrane protein 159::transmembrane protein 159 Hs H09934::H09933 IMAGE:46355 TMEM Hs TBC1 domain family, member 8B (with GRAM domain)::tbc1 domain family, member 8B (with GRAM domain) Hs AA287032::AA IMAGE: TBC1D8B Hs RAS-like, estrogen-regulated, growth inhibitor::ras-like, estrogen-regulated, growth inhibitor Hs AA IMAGE: RERG Hs Transforming growth factor, alpha::transforming growth factor, alpha Hs AA IMAGE: TGFA Hs Acyl-CoA thioesterase 7::acyl-CoA thioesterase 7::Transcribed locus Hs ::Hs AA035455::AA IMAGE: ACOT Hs insulin receptor::insulin receptor Hs T47312::T47311 IMAGE:70749 INSR Hs Caldesmon 1::caldesmon 1::Transcribed locus Hs ::Hs AA426421::AA IMAGE: CALD Hs Homo sapiens, clone IMAGE: , mrna Hs H19307::H19013 IMAGE: Hs Family with sequence similarity 13, member A1::family with sequence similarity 13, member A1 Hs AA IMAGE: FAM13A Page 11 of 22

12 Hs Transcribed locus Hs AA IMAGE: Hs Integrin, alpha 2 (CD49B, alpha 2 subunit of VLA-2 receptor)::integrin, alpha 2 (CD49B, alpha 2 subunit of VLA-2 receptor) Hs AA IMAGE: ITGA Hs Aldehyde dehydrogenase 3 family, member A2::aldehyde dehydrogenase 3 family, member A2 Hs AA418697::AA IMAGE: ALDH3A Hs Aldehyde oxidase 1::aldehyde oxidase 1 Hs AI IMAGE: AOX Hs Transforming, acidic coiled-coil containing protein 1::transforming, acidic coiled-coil containing protein 1 Hs AA IMAGE: TACC Hs Caldesmon 1::caldesmon 1 Hs H52087::H51958 IMAGE: CALD Hs Sema domain, transmembrane domain (TM), and cytoplasmic domain, (semaphorin) 6A::sema domain, transmembrane domain (TM), and cytoplasmic domain, (semaphorin) 6A Hs AA236561::AA IMAGE: SEMA6A 3980 Hs Chromosome 11 open reading frame 57::chromosome 11 open reading frame 57::Transcribed locus, strongly similar to NP_ hypothetical protein LOC55216 isoform b [Homo sapiens] Hs ::Hs W04502::W31402 IMAGE: C11orf Hs ST8 alpha-n-acetyl-neuraminide alpha-2,8-sialyltransferase 4::ST8 alpha-n-acetyl-neuraminide alpha-2,8-sialyltransferase 4 Hs AA IMAGE: ST8SIA Hs Yippee-like 2 (Drosophila)::yippee-like 2 (Drosophila) Hs AA IMAGE: YPEL Hs.7946 Mitochondrial tumor suppressor 1::mitochondrial tumor suppressor 1 Hs AA496896::AA IMAGE: MTUS Hs RAB11 family interacting protein 3 (class II)::RAB11 family interacting protein 3 (class II) Hs R44896::R24299 IMAGE:33977 RAB11FIP Hs.4104 Chromosome 14 open reading frame 129::chromosome 14 open reading frame 129::Transcribed locus Hs ::Hs AA233790::AA IMAGE: C14orf Page 12 of 22

13 Hs Transmembrane and tetratricopeptide repeat containing 1::transmembrane and tetratricopeptide repeat containing 1 Hs AA447480::AA IMAGE: TMTC Hs.904 Amylo-1, 6-glucosidase, 4-alpha-glucanotransferase (glycogen debranching enzyme, glycogen storage disease type III)::amylo-1, 6-glucosidase, 4-alphaglucanotransferase Hs AA IMAGE: AGL Hs Stanniocalcin 1::stanniocalcin 1 Hs AA085319::AA IMAGE: STC Hs CD52 molecule::cd52 molecule Hs AI IMAGE: CD Hs Actin binding LIM protein 1::actin binding LIM protein 1 Hs T50244::AI IMAGE:77325 ABLIM Hs Family with sequence similarity 13, member A1::family with sequence similarity 13, member A1 Hs AA024827::AA IMAGE: FAM13A Hs Endothelin receptor type B::endothelin receptor type B Hs H28710::H28840 IMAGE:49665 EDNRB Hs Solute carrier family 1 (glial high affinity glutamate transporter), member 3::solute carrier family 1 (glial high affinity glutamate transporter), member 3 Hs AA453742::AA IMAGE: SLC1A Hs Nonmetastatic cells 1, protein (NM23A) expressed in::nonmetastatic cells 1, protein (NM23A) expressed in Hs AA IMAGE: NME Hs Endothelial PAS domain protein 1::endothelial PAS domain protein 1 Hs AA IMAGE: EPAS Hs GNAS complex locus::gnas complex locus Hs AA035620::AA IMAGE: GNAS 6533 Hs Growth arrest-specific 2 like 3::growth arrest-specific 2 like 3 Hs AI IMAGE: GAS2 L Hs SUB1 homolog (S. cerevisiae)::sub1 homolog (S. cerevisiae) Hs AA456973::AA IMAGE: SUB Hs Dimethylarginine dimethylaminohydrolase 1::dimethylarginine dimethylaminohydrolase 1 Hs N24042::N35863 IMAGE: DDAH Page 13 of 22

14 Hs Zinc finger CCCH-type containing 6::zinc finger CCCH-type containing 6 Hs AA948719::AI733399::AI IMAGE: ZC3H Hs Major histocompatibility complex, class II, DR beta 3::major histocompatibility complex, class II, DR beta 1 Hs AA IMAGE: HLA-DRB Hs SLIT-ROBO Rho GTPase activating protein 2::SLIT-ROBO Rho GTPase activating protein 2 Hs N31484 IMAGE: SRGAP Hs SH3 domain binding glutamic acid-rich protein like 2::SH3 domain binding glutamic acid-rich protein like 2 Hs H19327::H19036 IMAGE:50926 SH3BGRL Hs Phosphoprotein associated with glycosphingolipid microdomains 1::phosphoprotein associated with glycosphingolipid microdomains 1 Hs H09567::H08999 IMAGE:45934 PAG Hs Transforming, acidic coiled-coil containing protein 1::transforming, acidic coiled-coil containing protein 1 Hs AA456316::AA IMAGE: TACC Hs N-acetylneuraminate pyruvate lyase (dihydrodipicolinate synthase)::n-acetylneuraminate pyruvate lyase (dihydrodipicolinate synthase) Hs W78156::W79930 IMAGE: NPL Hs Proprotein convertase subtilisin/kexin type 6::proprotein convertase subtilisin/kexin type 6::Proprotein convertase subtilisin/kexin type 6 Hs ::Hs W85807::W85806 IMAGE: PCSK Hs Sortilin-related receptor, L (DLR class) A repeats-containing::sortilin-related receptor, L (DLR class) A repeats-containing Hs AA IMAGE: SORL Hs Actin binding LIM protein 1::actin binding LIM protein 1 Hs AI IMAGE: ABLIM Hs Small G protein signaling modulator 3::small G protein signaling modulator 3 Hs AA IMAGE: SGSM Hs Transcribed locus Hs T61428 IMAGE: Hs Egl nine homolog 3 (C. elegans)::egl nine homolog 3 (C. elegans) Hs R00226::R00332 IMAGE: EGLN Page 14 of 22

15 Hs Transmembrane protein 27::transmembrane protein 27 Hs AA999850::AI IMAGE: TMEM Hs Integrin, alpha 6::integrin, alpha 6 Hs T54663::T54750 IMAGE:73784 ITGA Hs Transmembrane protein 27::transmembrane protein 27 Hs AI253234::AI793193::AI IMAGE: TMEM Hs KIAA0999 protein::kiaa0999 protein Hs AA446193::AA IMAGE: KIAA Hs EH domain binding protein 1::EH domain binding protein 1 Hs AA456284::AA IMAGE: EHBP Hs GNAS complex locus::gnas complex locus Hs AI IMAGE: GNAS 7441 Hs Ral guanine nucleotide dissociation stimulator-like 1::ral guanine nucleotide dissociation stimulator-like 1 Hs T98762::T98761 IMAGE: RGL Hs Cyclin-dependent kinase inhibitor 1B (p27, Kip1)::cyclin-dependent kinase inhibitor 1B (p27, Kip1) Hs AA192725::AA IMAGE: CDKN1B Hs Hepatic leukemia factor::hepatic leukemia factor Hs N70235::W00959 IMAGE: HLF 7753 Hs Sortilin-related receptor, L (DLR class) A repeats-containing::sortilin-related receptor, L (DLR class) A repeats-containing Hs N50656::N50751 IMAGE: SORL Hs Solute carrier family 36 (proton/amino acid symporter), member 1::solute carrier family 36 (proton/amino acid symporter), member 1 Hs R00480::R00479 IMAGE: SLC36A Hs Stanniocalcin 1::stanniocalcin 1 Hs AA126561::AA IMAGE: STC Hs Vav 3 guanine nucleotide exchange factor::vav 3 guanine nucleotide exchange factor Hs H10045::H10098 IMAGE:46827 VAV Hs Vascular cell adhesion molecule 1::vascular cell adhesion molecule 1 Hs H07072::H07071 IMAGE:44477 VCAM Hs Iroquois homeobox 3::iroquois homeobox 3 Hs R55185::R55184 IMAGE: IRX Page 15 of 22

16 Hs Tumor necrosis factor, alpha-induced protein 6::tumor necrosis factor, alpha-induced protein 6 Hs W92764::W93163 IMAGE: TNFAIP Hs Angiogenin, ribonuclease, RNase A family, 5::angiogenin, ribonuclease, RNase A family, 5 Hs T60163::T60223 IMAGE:81417 ANG Hs Cytochrome b5 type A (microsomal)::cytochrome b5 type A (microsomal) Hs R91950::R92281 IMAGE: CYB5A Hs Lysyl oxidase::lysyl oxidase Hs W60414::W60413 IMAGE: LOX Hs CDNA clone IMAGE: Hs AA IMAGE: Hs myosin VB::Acetyl-Coenzyme A acyltransferase 2 Hs H07926::H08029 IMAGE:45376 MYO5B Hs Cadherin 1, type 1, E-cadherin (epithelial)::cadherin 1, type 1, E-cadherin (epithelial) Hs H97778 IMAGE: CDH Hs Growth factor receptor-bound protein 10::growth factor receptor-bound protein 10 Hs AA IMAGE: GRB Hs N-acetylneuraminate pyruvate lyase (dihydrodipicolinate synthase)::n-acetylneuraminate pyruvate lyase (dihydrodipicolinate synthase) Hs AA233620::AA IMAGE: NPL 8293 Hs insulin receptor::insulin receptor Hs AA001614::AA IMAGE: INSR Hs Ectonucleotide pyrophosphatase/phosphodiesterase 2 (autotaxin)::ectonucleotide pyrophosphatase/phosphodiesterase 2 (autotaxin) Hs AA476508::AA IMAGE: ENPP Hs AT rich interactive domain 5B (MRF1-like)::AT rich interactive domain 5B (MRF1-like) Hs AA135616::AA IMAGE: ARID5B Hs podocalyxin-like::podocalyxin-like::transcribed locus Hs.16426::Hs N64508::N80294 IMAGE: PODXL Hs vesicle-associated membrane protein 5 (myobrevin)::vesicle-associated membrane protein 5 (myobrevin) Hs AA IMAGE: VAMP Page 16 of 22

17 Hs Transcribed locus Hs AA IMAGE: Hs.8944 Procollagen C-endopeptidase enhancer 2::procollagen C-endopeptidase enhancer 2 Hs AA115742::AA IMAGE: PCOLCE Hs Growth arrest-specific 2 like 3::growth arrest-specific 2 like 3 Hs R84407 IMAGE: GAS2 L3 885 Hs Carboxymethylenebutenolidase homolog (Pseudomonas)::carboxymethylenebutenolidase homolog (Pseudomonas) Hs AA111975::AA IMAGE: CMBL Hs Peroxisome proliferator-activated receptor gamma, coactivator 1 alpha::peroxisome proliferator-activated receptor gamma, coactivator 1 alpha Hs N89673::W21597 IMAGE: PPARGC1A 8967 Hs CDNA FLJ26512 fis, clone KDN07513 Hs N76019::W04370 IMAGE: Hs Caldesmon 1::caldesmon 1 Hs H48508::H48677 IMAGE: CALD Hs CD34 molecule::cd34 molecule Hs H72113::H72215 IMAGE: CD Hs Chromosome 10 open reading frame 58::chromosome 10 open reading frame 58 Hs AI IMAGE: C10orf Hs CD36 molecule (thrombospondin receptor)::cd36 molecule (thrombospondin receptor) Hs N39161::N45238 IMAGE: CD Hs Phosphoprotein associated with glycosphingolipid microdomains 1::phosphoprotein associated with glycosphingolipid microdomains 1 Hs AA IMAGE: PAG Hs POU class 5 homeobox 1::POU class 5 homeobox 1 Hs AI IMAGE: POU5F Hs DEAD (Asp-Glu-Ala-Asp) box polypeptide 47::DEAD (Asp-Glu-Ala-Asp) box polypeptide 47 Hs AA432292::AA IMAGE: DDX Hs GNAS complex locus::gnas complex locus Hs H72932::H72533 IMAGE: GNAS Page 17 of 22

18 Hs Solute carrier family 47, member 1::solute carrier family 47, member 1 Hs W85883::W85967 IMAGE: SLC47A Hs ST8 alpha-n-acetyl-neuraminide alpha-2,8-sialyltransferase 4::ST8 alpha-n-acetyl-neuraminide alpha-2,8-sialyltransferase 4 Hs AA IMAGE: ST8SIA Hs.8364 Pyruvate dehydrogenase kinase, isozyme 4::pyruvate dehydrogenase kinase, isozyme 4 Hs T61792 IMAGE:78946 PDK4 943 Hs Integrin, alpha 6::integrin, alpha 6 Hs R43483::R17993 IMAGE:32493 ITGA Hs Transforming growth factor, beta receptor III::transforming growth factor, beta receptor III Hs N26658::N39809 IMAGE: TGFBR Hs Myelin protein zero-like 2::myelin protein zero-like 2 Hs AA IMAGE: MPZL Hs Endothelial PAS domain protein 1::endothelial PAS domain protein 1 Hs R32440::R24882 IMAGE: EPAS Hs Major histocompatibility complex, class II, DM alpha::major histocompatibility complex, class II, DM alpha Hs H42728::H42679 IMAGE: HLA-DMA Hs AT rich interactive domain 5B (MRF1-like)::AT rich interactive domain 5B (MRF1-like) Hs AA173611::AA IMAGE: ARID5B Hs Lectin, galactoside-binding, soluble, 2::lectin, galactoside-binding, soluble, 2 Hs AA IMAGE: LGALS Hs Ral guanine nucleotide dissociation stimulator-like 1::ral guanine nucleotide dissociation stimulator-like 1 Hs AA IMAGE: RGL Hs IQ motif containing K::IQ motif containing K::Transcribed locus Hs ::Hs R43873::R19521 IMAGE:33603 IQCK Hs Poliovirus receptor-related 3::poliovirus receptor-related 3::Transcribed locus Hs ::Hs T40950::T40020 IMAGE:61502 PVRL Page 18 of 22

19 Hs KIAA1147::KIAA1147::Transcribed locus, strongly similar to NP_ synaptoporin [Mus musculus] Hs ::Hs H98619::N25140 IMAGE: KIAA Hs Cytochrome P450, family 4, subfamily V, polypeptide 2::kallikrein B, plasma (Fletcher factor) 1 Hs W90457::W90456 IMAGE: KLKB Table E2. Definitions of Imaging Traits Trait No. Trait Name Trait Description Stage Dependency Trait Values 1 Tumor size Maximal cross sectional diameter of the tumor (cm) Dependent Quantitative* 2 Renal capsule involvement Renal capsule involvement: does the tumor involve the renal capsule (yes/no) Dependent Binary 3 Gerota s fascia involvement Gerota fascia involvement: does the tumor invade or involve Gerota s fascia (yes or no) Dependent Binary 4 Infiltration of peritumoral fat Tumoral Infiltration of peritumoral fat (present or absent) Dependent Binary 5 Local Invasion Invasion of the tumor into the surrounding organs (present or absent) Dependent Binary 6 Renal vein thrombosis Renal vein thrombosis (present or absent) Dependent Binary 7 Enlarged lymph nodes Enlarged perirenal lymph nodes > 1 cm in long axis, present or absent, if present, Quantitative number of involved nodes. 8 Intratumoral Hemorrhage Areas of intratumoral hemorrhage on the precontrast scan (present/absent) Binary 9 Calcifications Intratumoral calcifications (present or absent) Binary 10 Pattern of enhancement Pattern of tumor enhancement involving > 50% of tumor area (homogeneous or heterogeneous) Binary Page 19 of 22

20 11 Low attenuation, precontrast Attenuation on precontrast image (least attenuating area) measured with 1-cm circle Quantitative* phase ROI 12 High attenuation, precontrast Attenuation on precontrast image (most attenuating area) measured with 1-cm circle Quantitative* phase ROI 13 Low attenuation, postcontrast Attenuation on postcontrast image (least attenuating area) measured with 1-cm Quantitative* phase circle ROI 14 High attenuation postcontrast Attenuation on postcontrast image (most attenuating area) measured with 1-cm Quantitative* phase circle ROI 15 Attenuation change, low Attenuation on postcontrast image corresponding to same ROI measured on 11 above Quantitative* 16 Attenaution change, high Attenuation on postcontrast image corresponding to same ROI measured on 12 above measured with 1 cm circle ROI Quantitative* 17 Pattern of tumor necrosis Pattern of tumor necrosis: percentage tumor necrosis: (0% 25%, 26% 50%, 51% 75%, 76% 100%) Ordinal 18 Tumor margins Tumor margins (sharply defined or ill defined) Binary 19 Tumor contour Tumor confined within the renal contour or exophytic Binary 20 Tumor shape Circumscribed versus infiltrative Binary 21 Location Tumor Location: upper, mid, or lower pole Ordinal 22 Involvement of renal pelvis Involvement or invasion of the tumor into the renal pelvis: present or absent Binary 23 Tumor number Number of discrete, noncontiguous tumors in the target kidney Quantitative 24 Presence of distant metastasis Distant mets: presence or absence of visible lesions suspicious for metastasis with in the visualized chest or abdomen Dependent Binary Page 20 of 22

21 25 Nonintrinsic RCC features Presence of absence of findings in target kidney not directly related to the target lesion such as renal cysts or renal stones Binary 26 Tumor transition zone Tumor transition zone: An assessment of the transition zone from tumor tissue to renal parenchyma tissue, scored as either the presence or absence of a clearly demarcated tumor, in its entirety, with a sharply defined transition between tumor and renal parenchyma. Binary 27 Ratio of contrast to necrosis Ratio of contrast to necrosis where mild has a ratio 1: Contrast enhancing volume is equal to or greater than necrosis volume, where moderate, the ratio is approximately 1, and severe where the ratio is less than 1: contrast enhancing volume is significantly less than the necrosis volume Ordinal 28 Tumor heterogeneity, Tumor heterogeneity on the precontrast image is mild, moderate, or severe Ordinal precontrast phase 29 Tumor heterogeneity, Tumor heterogeneity on the postcontrast image is mild, moderate, or severe Ordinal postcontrast phase 30 Tumor-parenchyma interaction Tumor-parenchyma interaction: A discrete rim of enhancement partially or completely circumscribing the tumor on equilibrium phase imaging in the absence of a hypoattenuating rim Binary 31 Tumor-parenchyma interface Tumor-parenchyma interface: A hypoattenuating rim completely or partially circumscribing the tumor on equilibrium phase imaging. Binary 32 Internal vascularity Internal arteries: The presence or absence of discrete enhancing arteries within the tumor Binary 33 Internal architecture Internal septations: the presence or absence of fibrous septations within the tumor Binary Page 21 of 22

22 34 Tumor hypoxia1 Internal arteries in areas of necrosis: The presence or absence of internal arteries in regions of tumor necrosis Binary 35 Tumor hypoxia2 Internal arteries at the edge of regions of necrosis: The presence or absence of internal arteries extending up to the edge of a region of necrosis Binary Note. ROI = region of interest. * Real numbers. Integer. Page 22 of 22