Poster Sessions

Epi-14

Linda Dong

L. Dong, P. Brennan, S. Karami, I. Menashe, S. Berndt, M. Yeager, S. Chanock, D. Zaridze, V. Matteev, V. Janout, H. Kollarova, V. Bencko, M. Navratilova, N. Szeszenia-Dabrowska, I. Holcatova, P. Boffetta, N. Rothman, W. H. Chow, P. Rosenberg, L. Moore

Comprehensive analysis of candidate growth, differentiation and apoptosis genes with risk of renal cancer in the Central and Eastern European Renal Cancer Study

Evidence suggests that variation in genes involved in cellular growth, differentiation and apoptosis may increase susceptibility to cancer. We conducted a case-control study of renal cancer (987 cases and 1298 controls) in Central and Eastern Europe and analyzed genomic DNA for 319 tagging single-nucleotide polymorphisms(SNPs) in 21 candidate genes involved in cellular growth, differentiation and apoptosis using an Illumina Oligo Pool-All (OPA). A haplotype-based method (sliding window analysis of three consecutive SNPs) was used to identify chromosome regions of interest that remained significant at a false discovery rate of 10%. Subsequently, risk estimates were generated for regions using unconditional logistic regression with a high level of signal using Haplostats. Four genes with regions that were associated with renal cancer were identified: CASP1/5/4/12, EGFR, IGFBP3, and VCAM1. We observed that individuals with CASP1/5/4/12 haplotype GGGCTCAGT (OR:1.40, 95% CI:1.10-1.78) were at higher risk of renal cancer compared to individuals with the most common haplotype. Analysis of EGFR revealed three strong signals within intron 1, particularly an area centered around rs759158 (GGG: OR:1.26, 95% CI:1.04-1.53 and ATG: OR:1.55, 95% CI:1.14-2.11). In the region between exon 2 and 4848bp 3\' of IGFBP3, variant AAAGC was associated with increased renal cancer risk (OR:1.49, 95% CI:1.14-1.95). Concordant with haplotype analyses, significant associations for individual SNPs were observed within all four genes. The strongest association was nonsynonymous SNP CASP5 rs507879(T90A). The ORs(95% CI) for heterozygote and homozoygote rare genotypes was 1.29(1.03-1.60) and 1.39(1.07-1.82; trend =0.01). Review of the literature suggests that these findings are biologically plausible. Despite being the largest, this is the first study to evaluate these genes in relation to RCC and there is need to replicate and extend our findings.