Abstract A89: Association of genes involved in lipid metabolism-peroxidation and risk of renal cancer in the Central European Renal Cancer Case-Control Study

Abstract

Abstract A89 Recent descriptive studies have reported increases in kidney cancer incidence since the 1970s in the United States and globally. Lipid peroxidation has been suggested as a unifying mechanistic pathway by which several known risk factors including obesity, hypertension, and chemicals directly damage cells of the proximal renal tubules and induce renal carcinogenesis. This study investigated the association between renal cell cancer (RCC) risk and variation in genes that modify the effects of lipid peroxidation, inflammation, and oxidative stress. We conducted a case-control study of RCC (987 cases and 1298 controls) from Central and Eastern Europe and analyzed genomic DNA for 635 single nucleotide polymorphisms (SNPs) thirty-eight candidate genes using an Illumina Oligo Pool-All (OPA). First, the minimum p-value permutation test (MINP) was used to identify genes that remained significant with an FDR<5%. Subsequently, a haplotype-based sliding window analysis of three consecutive SNPs was used to identify chromosome regions of interest that remained significant at a FDR<5%. Six genes were selected for in-depth analysis after multiple testing correction of the single marker associations: APOE, GPX4, NOS2A and PTGS2. The overall gene-level p-values for these genes were 0.017, 0.020, 0.055 and 0.069 using the MINP test, respectively. The minimum FDR-adjusted p-values in a sliding window haplotype analysis were 0.0005, 0.0007, 0.0002 and 1.09x10-5, respectively. For these regions, age-, sex- and center-adjusted haplotype relative risks were computed using the HaploStats package in R. After adjustment, a strong signal centered around the promoter region of APOE gene (rs405509) remained significantly associated with decreased risk of RCC compared to persons homozygous for the referent haplotype (OR=0.73 95% CI:0.59-0.91); global p=0.001). A second haplotype window spanning from IVS7+11 to IVS12-52 of the NOS2A gene that was significantly associated with increased risk (OR=1.36 (95% CI:1.05-1.78); p-global p-0.006). Additional haplotype windows spanning the trans-membrane and tyrosine kinase domains of INSR (rs28601) and intron 2 of LEPR (rs970467) genes also were investigated further (FDR-adjusted p <0.05). After adjustment in Haplostats, two additional high risk haplotypes were identified that were significantly associated with risk. To our knowledge this is the first and largest study of RCC conducted to evaluate these genes in relation to RCC. Although replication and fine mapping studies will be required to confirm these findings, this study supports the hypothesis variation in genes influencing lipid metabolism/peroxidation may increase susceptibility to sporadic kidney cancer. Citation Information: Cancer Prev Res 2008;1(7 Suppl):A89.