Apolipoprotein E/C1 locus variants modify renal cell carcinoma risk

Lee E. Moore, Paul Brennan, Sara Karami, Idan Menashe, Sonja I. Berndt, Linda M. Dong, Allison Meisner, Meredith Yeager, Stephen Chanock, Joanne Colt, Kendra Schwartz, Faith Davis, David Zaridze, Vsevolod Mattveev, Vladimir Janout, Hellena Kollarova, Vladimir Bencko, Marie Navratilova, Neonilia Szeszenia-Dabrowska, Dana MatesIvana Holcatova, Paolo Boffetta, Wong Ho Chow, Philips Rosenberg, Nathaniel Rothman

Research output: Contribution to journalArticlepeer-review

Abstract

Lipid peroxidation is considered a unifying mechanistic pathway through which known risk factors induce renal cell carcinoma (RCC). We hypothesized that genes selected a priori for their role in lipid peroxidation would modify cancer risk. We genotyped 635sin gle nucleotide polymorphisms (SNP) in 38 candidate genes in 777 Caucasian RCC cases and 1,035 controls enrolled in a large European case-control study. Top candidate SNPs were confirmed among 718 Caucasian cases and 615controls in a second study in the United States. Two of the three SNPs (rs8106822 and rs405509) that replicated in the U.S. study were within a regulatory region of the APOE promoter. The OR for rs8106822 A>G variant was 1.22AG and 1.41GG (Ptrend = 0.01) in the European study, 1.05AG and 1.51GG (P trend = 0.03) in the U.S. study, and 1.15AG and 1.44 GG (Ptrend = 0.001) among 1,485 cases and 1,639 controls combined. The rs405509 G>T variant was associated with risk in the European (OR, 0.87TG; OR, 0.71TT; Ptrend = 0.02), the U.S. (OR, 0.68TG; OR, 0.71TT; Ptrend = 0.02), and both studies combined (ORTG, 0.79; ORTT, 0.71; Ptrend = 0.001), as was the G-G haplotype (r2 = 0.64; P = 4.7 × 10-4). This association is biologically plausible as SNP rs405509 was shown to modify protein binding and transcriptional activity of the APOE protein in vitro and is in linkage disequilibrium with key known variants defining the e2, e3, and e4 alleles that modify risk of atherosclerosis, Alzheimer's disease risk, and progression to AIDS. In two large case-control studies, our findings further define a functional region of interest at the APOE locus that increases RCC susceptibility.

Original languageEnglish (US)
Pages (from-to)8001-8008
Number of pages8
JournalCancer Research
Volume69
Issue number20
DOIs
StatePublished - Oct 15 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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