Identification of Recurrent Mutations in the microRNA-Binding Sites of B-Cell Lymphoma-Associated Genes in Follicular Lymphoma
Enright, Anton J.
International Journal of Molecular Sciences
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Larrea, E., Fernandez-Mercado, M., Guerra-Assunção, J. A., Wang, J., Goicoechea, I., Gaafar, A., Ceberio, I., et al. (2020). Identification of Recurrent Mutations in the microRNA-Binding Sites of B-Cell Lymphoma-Associated Genes in Follicular Lymphoma. International Journal of Molecular Sciences, 21 (22)https://doi.org/10.3390/ijms21228795
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).
follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), microRNA, mutation
External DOI: https://doi.org/10.3390/ijms21228795
This record's URL: https://www.repository.cam.ac.uk/handle/1810/313214