Targetome Profiling, Pathway Analysis and Genetic Association Study Implicate miR-202 in Lymphomagenesis

Background: miRNAs have been implicated in numerous tumorigenic pathways, and previous studies have associated miR-202 dysregulation with various cancer types, including follicular lymphoma. Methods: The miR-202 targetome was identified by ribonucleoprotein immunoprecipitation-microarray (RIP-Chip), and functional interactions among identified targets were investigated using the Ingenuity Pathway Analysis tool. We also conducted a population-based genetic association study of a polymorphism within the miR-202 stem-loop sequence and risk of non-Hodgkin lymphoma. In vitro gain-of-function experiments were further conducted to elucidate the functional significance of the variant. Results: A total of 141 potential members of the miR-202 targetome were identified by a transcriptome-wide RIP-Chip assay. Functional interactions among identified targets suggested that miR-202-regulated genes are involved in biologic pathways relevant for hematologic function and cancer. Consistent with this, a genetic association analysis using human blood samples revealed a significant association between a germline mutation (rs12355840) in the miR-202 precursor sequence and follicular lymphoma risk. An in vitro functional assay further showed that the variant allele resulted in diminished miR-202 levels, possibly by altering precursor-processing efficiency. Conclusions: Taken together, our findings suggest that miR-202 is involved in follicular lymphomagenesis. Impact: These findings implicate miR-202 as a potential tumor suppressor in follicular lymphoma and warrant the investigation of miR-202 as a novel biomarker of follicular lymphoma risk. Cancer Epidemiol Biomarkers Prev; 22(3); 327-36. (C)2013 AACR.