MicroRNA Polymorphisms and Risk of Colorectal Cancer

Stephanie L Schmit, Jeremy Gollub, Michael H Shapero, Shu-Chen Huang, Hedy S Rennert, Andrea Finn, Gad Rennert, Stephen B Gruber

Background: MicroRNAs (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-messenger RNA interaction and subsequently alter risk of cancer development. Methods: This study expanded the search for miRNA-related polymorphisms contributing to the etiology of colorectal cancer (CRC) across the genome using a novel platform, the Axiom® miRNA Target Site Genotyping 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 CRC in northern Israel. The association between each marker and CRC 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-value=3.7E-05). Further, this study replicated a previously published locus, rs1051690 in the 3'-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 CRC 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 CRC. Impact:This study demonstrates the potential for a miRNA-targeted genome-wide association study to identify candidate susceptibility loci and prioritize them for functional characterization.