Abstract LB-330: Genetic variants in the 9p21 region in relation to the risk of multiple tumors

Abstract

Abstract Chromosome 9p21 has been implicated in the pathogenesis of cutaneous malignant melanoma (CMM), glioma, non-small cell lung cancer, and leukemia. This region includes cyclin-dependent kinase inhibitor 2A (CDKN2A), the major known high-risk susceptibility gene for CMM; CDKN2B; antisense noncoding RNA in the INK4 locus (ANRIL), a GWAS hotspot for multiple phenotypes including cancers; methylthioadenosine phosphorylase (MTAP), a gene with tumor suppressor function and a cluster of type I interferon (IFN) genes. The goal of this study was to examine the association between genetic variation in the 9p21 region and multiple cancer outcomes using genotyping data from studies participating in the National Cancer Institute's (NCI) iSelect project. We evaluated up to 202 tagSNPs in 22 genes in the 9p21 region (19.9-32.8 Mb), in case-control studies of thyroid cancer (THC), endometrial cancer (EC), testicular cancer (TC), renal cell carcinoma (RCC), colorectal cancer (CRC), colorectal adenoma (CA), esophageal squamous cell carcinoma (ESCC), gastric cardia cancer (GCC) and osteosarcoma (OS). The number of cases in each of the nine studies ranged from 96 to 1234. We first performed single SNP-based analyses for each study separately, using logistic regression adjusted for age and study-specific covariates. To combine SNP based analyses, we used a newly developed subset-based statistical approach (ASSET), which allow for heterogeneity of SNP effect on different outcomes. This approach exhaustively explores subsets of studies for the presence of association signals, and then evaluates the significance from subsets with the strongest association signal, meanwhile accounting for multiple tests required by the subset search. Gene based P-values were computed using an adaptive rank truncated product (ARTP) statistic and a permutation-based sampling procedure (10,000 permutations) that took into account the numbers of SNPs in each gene and their linkage disequilibrium structure. When analyzing each study separately, we found that a SNP (rs3731257) in CDKN2A was significantly associated with the risk of ESCC after Bonferroni correction for number of SNPs and studies (P=7 x 10-6). Meta-analyses by ASSET found that this SNP was significantly associated with both ESCC and EC (PASSET<10-4). In addition, several SNPs in genes CDKN2A, CDKN2B, MTAP, and ANRIL were suggestively associated with multiple tumor outcomes in the same direction. At the gene level, CDKN2A was significantly associated with ESCC (Pgene = 0.0001). In conclusion, our data suggest that several variants in CDKN2A and possibly other genes that are located in the close vicinity may be associated with ESCC and several other tumors. Results from our study further highlight the importance of the 9p21 region in the development of multiple tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-330. doi:1538-7445.AM2012-LB-330