title: Targetome profiling and functional genetics implicate miR-618 in lymphomagenesis.
abstract: 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.
authors: Department of Environmental Health Sciences; Yale School of Public Health; New Haven, CT USA.
authors: Alan
authors: A
authors: Fu
authors: Department of Epidemiology; Tulane School of Public Health and Tropical Medicine and Tulane Cancer Center; New Orleans, LA USA.
authors: Aaron E
authors: AE
authors: Hoffman
authors: Department of Environmental Health Sciences; Yale School of Public Health; New Haven, CT USA; Key Laboratory of Environmental Medicine Engineering; Ministry of Education; School of Public Health; Southeast University; Nanjing, PR China.
authors: Ran
authors: R
authors: Liu
authors: Department of Environmental Health Sciences; Yale School of Public Health; New Haven, CT USA.
authors: Daniel I
authors: DI
authors: Jacobs
authors: Department of Environmental Health Sciences; Yale School of Public Health; New Haven, CT USA.
authors: Tongzhang
authors: T
authors: Zheng
authors: Department of Environmental Health Sciences; Yale School of Public Health; New Haven, CT USA.
authors: Yong
authors: Y
authors: Zhu
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D023281:Genomics; D006367:HeLa Cells; D006801:Humans; D008224:Lymphoma, Follicular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D035683:MicroRNAs / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C588068:MIRN618 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger
keywords: follicular lymphoma; lymphomagenesis; miR-618; pathway analysis; targetome