Targetome profiling and functional genetics implicate miR-618 in lymphomagenesis.

Despite the voluminous body of observational evidence concerning the role of miRNAs in cancer, significant knowledge gaps remain concerning the molecular circumstances that underlie the miRNA-cancer connection. In this study, we employ a multidisciplinary approach to establish an association between miR-618 and non-Hodgkin lymphoma (NHL) in a human population and attempt to explicate this association at the molecular level. A high-throughput, transcriptome-wide RIP-Chip-based method was used to identify members of the miR-618 targetome, which were analyzed for functional relevance using a gene network-based approach. Findings were confirmed by genotyping a SNP (rs2682818) in the stem-loop sequence of miR-618 in a population-based case-control study of NHL (455 cases and 527 controls). Lastly, we analyzed the functional impact of rs2682818 on miR-618 expression and its consequent implications for the lymphomagenic process. A total of 128 miR-618 targets were identified, which were enriched for genes that have functional roles in lymphoma-relevant pathways. This is consistent with our finding of a significant association between rs2682818 G>T in the miR-618 stem-loop and follicular lymphoma (FL) (OR: 1.65, 95% CI: 1.05-2.60). In vitro analysis of rs2682818's functional impact revealed that the variant T allele resulted in reduced levels of mature miR-618, which in turn may lead to deregulation of miR-618-controlled pathways relevant to follicular lymphoma. Taken together, our findings implicate miR-618 in follicular lymphomagenesis, identify miR-618 as a potential risk biomarker for follicular lymphoma, and illuminate miR-618-regulated lymphomagenic pathways that can serve as therapeutic targets for follicular lymphoma.