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

Published version
Peer-reviewed

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Authors

Larrea, Erika 
Fernandez-Mercado, Marta  ORCID logo  https://orcid.org/0000-0003-3458-9231
Guerra-Assunção, José Afonso  ORCID logo  https://orcid.org/0000-0001-6593-403X
Goicoechea, Ibai 

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).

Description

Keywords

follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), microRNA, mutation

Journal Title

International Journal of Molecular Sciences

Conference Name

Journal ISSN

1422-0067

Volume Title

21

Publisher

MDPI