1. Identification of Recurrent Mutations in the microRNA-Binding Sites of B-Cell Lymphoma-Associated Genes in Follicular Lymphoma.
- Author
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Larrea E, Fernandez-Mercado M, Guerra-Assunção JA, Wang J, Goicoechea I, Gaafar A, Ceberio I, Lobo C, Okosun J, Enright AJ, Fitzgibbon J, and Lawrie CH
- Subjects
- Cell Line, Tumor, Cohort Studies, Humans, London, Mutation, Retrospective Studies, Spain, Binding Sites, Enhancer of Zeste Homolog 2 Protein genetics, Lymphoma, Follicular genetics, Lymphoma, Large B-Cell, Diffuse genetics, MicroRNAs genetics, Proto-Oncogene Proteins c-bcl-2 genetics
- Abstract
Follicular lymphoma (FL) is a common indolent B-cell lymphoma that can transform into the more aggressive transformed FL (tFL). However, the molecular process driving this transformation is uncertain. In this work, we aimed to identify microRNA (miRNA)-binding sites recurrently mutated in follicular lymphoma patients, as well as in transformed FL patients. Using whole-genome sequencing data from FL tumors, we discovered 544 mutations located in bioinformatically predicted microRNA-binding sites. We then studied these specific regions using targeted sequencing in a cohort of 55 FL patients, found 16 recurrent mutations, and identified a further 69 variants. After filtering for QC, we identified 21 genes with mutated miRNA-binding sites that were also enriched for B-cell-associated genes by Gene Ontology. Over 40% of mutations identified in these genes were present exclusively in tFL patients. We validated the predicted miRNA-binding sites of five of the genes by luciferase assay and demonstrated that the identified mutations in BCL2 and EZH2 genes impaired the binding efficiency of miR-5008 and miR-144 and regulated the endogenous levels of messenger RNA (mRNA).
- Published
- 2020
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