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Identification of Recurrent Mutations in the microRNA-Binding Sites of B-Cell Lymphoma-Associated Genes in Follicular Lymphoma.

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Larrea, Erika 
Fernandez-Mercado, Marta  ORCID logo
Guerra-Assunção, José Afonso  ORCID logo


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).



diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), microRNA, mutation, Binding Sites, Cell Line, Tumor, Cohort Studies, Enhancer of Zeste Homolog 2 Protein, Humans, London, Lymphoma, Follicular, Lymphoma, Large B-Cell, Diffuse, MicroRNAs, Mutation, Proto-Oncogene Proteins c-bcl-2, Retrospective Studies, Spain

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Int J Mol Sci

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