Abstract 2560: MicroRNA target site polymorphisms and colorectal cancer risk in the Ashkenazi Jewish population.

Abstract

Abstract MicroRNAs (miRNAs) act as key post-transcriptional regulators of gene expression via binding to the 3’ untranslated regions (UTRs) of mRNAs. Single nucleotide polymorphisms (SNPs) found in the miRNA sequence and/or corresponding binding sites can affect the fidelity of this interaction, and evidence from candidate miRNA studies suggests that such SNPs may increase or decrease risk of tumor development. This study was designed to expand the search for miRNA-related polymorphisms important in cancer etiology across the genome and to investigate the association between thousands of genetic variants in miRNA target sites and colorectal cancer (CRC) risk using a novel genotyping platform, the Axiom® miRNA Target Site Genotyping Array (237,858 markers). The final study sample after quality control filtering included 605 cases and 615 controls from the Molecular Epidemiology of Colorectal Cancer (MECC) study, a population-based case-control study of incident CRC cases in a geographically-defined area of northern Israel. The marginal association between each marker with minor allele frequency >=1% and CRC risk was examined assuming a log-additive genetic model using logistic regression adjusted for sex, age, and the first two principal components (PC) to capture fine-scale population structure. There were 11 markers with p-values less than 3E-4, and the most statistically significant association involved rs12130051 (chr1:19545053; 3’-UTR of KIAA0090) with an OR of 2.24 (1.52,3.31) and p=4.48E-5. In addition, rs1051690 (chr5:142605172; 3’-UTR of ARHGAP26), was statistically significantly associated with decreased CRC risk (OR (95% CI): 0.71 (0.59, 0.85); p = 2.03E-4). Further, this study provided evidence for replication of a previously published locus, rs1051690 in the 3’UTR region of the insulin receptor gene, INSR (OR (95% CI): 1.27 (0.96,1.67); p = 0.09). A fixed-effects meta-analysis of sample-size weighted p-values from a recent publication in Carcinogenesis describing the INSR variant (Landi et al., 2012) and from the current MECC study yielded a combined p-value of 0.01. To our knowledge, this is the first study to examine the association between genetic variation in miRNA target sites and cancer risk using a genome-wide approach. Work is ongoing to replicate findings from this study and to characterize the functional impact of prioritized polymorphisms. Citation Format: Stephanie L. Stenzel, Jeremy Gollub, Michael Shapero, Andrea Finn, Gad Rennert, Stephen B. Gruber. MicroRNA target site polymorphisms and colorectal cancer risk in the Ashkenazi Jewish population. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2560. doi:10.1158/1538-7445.AM2013-2560