Abstract 4580: Targetome profiling, pathway analysis and genetic association study implicate miR-618 in follicular lymphomagenesis.
Authors: Alan Fu, Aaron E. Hoffman, Ran Liu, Daniel I. Jacobs, Tongzhang Zheng, Yong Zhu
Journal: Cancer Research (2013)

Abstract Background. The advent of small non-coding RNAs as important modulators of cancer susceptibility and progression has gained widespread recognition in recent years. This growing interest has fueled a considerable number of molecular and epidemiological undertakings to elucidate the role of miRNAs in human cancers, leading to an enhanced understanding of miRNA function in human carcinogenesis. However, efforts to engage the subject using high-throughput methods remain lacking. In this study, we demonstrate the viability of using a high-throughput target-screening approach to complement more traditional epidemiological methods in elucidating the lymphomagenic role of miR-618, the altered expression of which has been found in multiple cancers. Methods. We first performed a high-throughput, transcriptome-wide RIP-Chip-based assay to identify members of the miR-618 targetome, followed by network-based analysis to investigate disease-relevant networks. A germline mutation (rs2682818) in the miR-618 precursor was then genotyped in a population of non-Hodgkin lymphoma cases and population-based controls, followed by a vector-based in vitro assay to examine the functional impact of this mutation on miR-618 processing efficiency. Results. Our transcriptome-wide target screening identified 28 potential members of the miR-618 targetome, which we subsequently validated using a luciferase reporter assay. Interrogating identified targets for functional interrelatedness using the Ingenuity Pathway Analysis tool revealed a molecular network highly enriched for both B- and T-cell NHL-relevant molecules, including TP53 and BRCA1. Consistent with this observation, we found the presence of the germline polymorphism (rs2682818) in the stem-loop structure of the pre-miRNA to be significantly associated with both follicular (OR = 1.65, 95% CI: 1.05 - 2.60) and T-cell NHL (OR = 5.12, 95% CI: 1.23 - 21.40) in a population of 455 NHL cases and 527 population-based controls. Finally, a vector-based in vitro analysis of rs2682818′s functional impact revealed that the variant allele resulted in reduced levels of miR-618, possibly by attenuating pre-miRNA processing efficiency. This suggests that the presence of the variant allele may act to disrupt miR-618′s capacity to inhibit target mRNA transcripts, ultimately leading to the dysregulation of TP53 and BRCA1 lymphoma-relevant pathways. Conclusion. Taken together, our findings implicate miR-618 in follicular and T-cell lymphomagenesis, identify rs2682818 as a potential biomarker for follicular and T-cell non-Hodgkin lymphoma, and illuminate a potential mechanism by which disease may be conferred. Moreover, we demonstrate the value of applying a high-throughput target screening technique to complement more traditional epidemiological methods in miRNA cancer biomarker identification. Citation Format: Alan Fu, Aaron E. Hoffman, Ran Liu, Daniel I. Jacobs, Tongzhang Zheng, Yong Zhu. Targetome profiling, pathway analysis and genetic association study implicate miR-618 in follicular lymphomagenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4580. doi:10.1158/1538-7445.AM2013-4580