Genome-wide association study of renal cell carcinoma identifies two susceptibility loci on 2p21 and 11q13.3

Abstract

contributed to the design and execution of the overall study. M.P.P., M.J., J.R.T., G.S., L.E.M., L.A.K., X.W., V.G., K.B.J., J.D.M., N.R., S.J.C., and P Brennan contributed to the statistical analysis. M.P.P., M.J., S.J.C. and P. Brennan wrote the first draft of the manuscript. D. Zeleniak, E.P., L.A.K., X.W., K.B.J., S.H.V., S.L.M., Y.Y., A.M.M., E.S.B., N.N.C., M.F., D.L., I.G., S.H., H. Blanche, A.H., G.T., Z.W., M.Y., K.G.S., S.J.C., and M.L. supervised or conducted the genotyping. The remaining authors conducted the epidemiologic studies and contributed samples to the GWAS and/or replication. All authors contributed to the writing of the manuscript. NIH Public Access Author ManuscriptNat Genet. Author manuscript; available in PMC 2012 January 1. AbstractWe conducted a two-stage genome-wide association study of renal cell carcinoma (RCC) in 3,772 cases and 8,505 controls of European background from 11 studies, and followed up 6 SNPs in three replication studies of 2,198 cases and 4,918 controls. Two loci on the regions of 2p21 and 11q13.3 were associated with RCC susceptibility below genome-wide significance. Two correlated variants (r 2 = 0.99 in controls), rs11894252 (P = 1.8×10 −8 ) and rs7579899 (P = 2.3×10 −9 ), map to EPAS1 on 2p21, which encodes hypoxia-inducible-factor-2 alpha, a transcription factor previously implicated in RCC. The second locus, rs7105934, at 11q13, contains no characterized genes (P = 7.8×10 −14 ). In addition, we observed a promising association on 12q24.31 for rs4765623 which maps to the scavenger receptor class B, member 1 (SCARB1) gene (P = 2.6×10 −8 ). Our study reports novel genomic regions associated with RCC risk that may lead to new etiological insights. Table 1, Online Methods and Supplementary note). All subjects from the IARC/CNG study were genotyped at the CNG with the exception of 305 cases and 323 controls from Russia that were genotyped at the Center "Bioengineering" and at the "Kurchatov Institute" in Moscow. All subjects from the NCI study were scanned at the NCI Core Genotyping Facility. In addition, 1,438 controls from the Wellcome Trust Case-Control Consortium were genotyped at the Sanger Institute, UK 10 . All RCC cases were defined on the basis of the International Classification of Diseases for Oncology, Second Edition (ICD-O-2), and included all cancers that were coded as C64.Comparable quality control metrics were applied to the two scanned data sets and following sample and SNP exclusions, genotype data for up to 577,547 SNPs were available for 2,461 cases and 5,081 controls in the IARC/CNG scan, while data for 585,576 SNPs were available for 1,311 cases and 3,424 controls in the NCI scan (Online Methods). Primary analyses were conducted using unconditional logistic regression models for genotype trend effects (1 degree of freedom) and adjusted for sex, country, eigenvectors, and study for the USA (Online Methods). In order to compute summary findings across both scans, a metaanalysis was performed using a fixed effects model with inverse variance wei...

VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma

“…A cell line was derived from the tumor tissue, and its histone profile is displayed below its matching primary tissue. This enhancer is known to interact with the CCND1 promoter from a previous study (21) and is situated close to an RCC susceptibility SNP rs7105934 (49).…”

Variation in genomic landscape of clear cell renal cell carcinoma across Europe

“…A modest proportion (2-4%) of RCC is associated with VHL syndrome caused by germline mutations in VHL 5 . Results from genome-wide association studies have identified common germline variants associated with increased susceptibility for developing ccRCC 6,7 , and recent sequencing efforts have revealed recurrent somatic mutations in a number of genes including PBRM1, SETD2 and BAP1 (ref. 8).…”

A common variant at 8q24.21 is associated with renal cell cancer

“…According to our RCC GWAS data set, association results for four 5,6 of the five previously reported GWAS-identified RCC susceptibility variants are confirmed (P between 0.011 and 3.0 Â 10 À 4 for SNPs on 2p12, 11q13.3, 12p11.23 and 12q24.31 (Table 1) generated from logistic regression analysis). Logistic regression is used throughout to test for association between SNPs and disease.…”

“…Rare, high-penetrance mutations accounting for syndromic RCC have been found in several genes, including VHL, MET, FLCN and FH 4 . Genome-wide association studies (GWAS) have reported five sporadic RCC susceptibility loci [5][6][7] . However, in combination, these risk variants account for only a small fraction of the approximately twofold greater than the average risk of RCC in first-degree relatives of RCC patients 1,2 .…”