Gaafar, A. (Ayman)

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    Identification of Recurrent Mutations in the microRNA-Binding Sites of B-Cell Lymphoma-Associated Genes in Follicular Lymphoma
    (2020) Wang, J. (Jun); Fernandez-Mercado, M. (Marta); Goicoechea, I. (Ibai); Larrea, E. (Erika); Guerra-Assunção, J.A. (José Afonso); Ceberio, I. (Izaskun); Enright, A.J. (Anton J.); Fitzgibbon, J. (Jude); Gaafar, A. (Ayman); Lawrie, C.H. (Charles H.); Lobo, C. (Carmen); Okosun, J. (Jessica)
    : 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).