MicroRNA Polymorphisms and Risk of Colorectal Cancer

Background: miRNAs act as post-transcriptional regulators of gene expression. Genetic variation in miRNA-encoding sequences or their corresponding binding sites may affect the fidelity of the miRNA-mRNA interaction and subsequently alter the risk of cancer development. Methods: This study expanded the search for miRNA-related polymorphisms contributing to the etiology of colorectal cancer across the genome using a novelplatform, the AxiommiRNATarget SiteGenotyping Array (237,858 markers). After quality control, the study included 596 cases and 429 controls from the Molecular Epidemiology of Colorectal Cancer study, a population-based case-control study of colorectal cancer in northern Israel. The association between each marker and colorectal cancer status was examined assuming a log-additive genetic model using logistic regression adjusted for sex, age, and two principal components. Results: Twenty-three markers had P values less than 5.0E 04, and the most statistically significant association involved rs2985 (chr6: 34845648; intronic of UHRF1BP1; OR 0.66; P 3.7E 05). Furthermore, this study replicated a previously published risk locus, rs1051690, in the 30-untranslated region of the insulin receptor gene INSR (OR 1.38; P 0.03), with strong evidence of differences in INSR gene expression by genotype. Conclusions: This study is the first to examine associations between genetic variation in miRNA target sites and colorectal cancer using a genome-wide approach. Functional studies to identify allele-specific effects on miRNA binding are needed to confirm the regulatory capacity of genetic variation to influence risk of colorectal cancer. Impact: This study demonstrates the potential for an miRNA-targeted genome-wide association study to identify candidate susceptibility loci and prioritize them for functional characterization. Cancer Epidemiol Biomarkers Prev; 24(1); 65-72. 2014 AACR.