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Coding and regulatory drivers of mantle cell lymphoma identified through exome and genome sequencing

By Prasath Pararajalingam, Krysta M Coyle, Sarah E Arthur, Nicole Thomas, Miguel Alcaide, Barbara Meissner, Merrill Boyle, Bruno Grande, Graham Slack, Andrew J. Mungall, Randy D Gascoyne, Christian Steidl, Joseph Connors, Diego Villa, Marco A. Marra, Nathalie Johnson, David W Scott, Ryan D. Morin

Posted 08 Jul 2019
bioRxiv DOI: 10.1101/686956 (published DOI: 10.1182/blood.2019002385)

Mantle cell lymphoma (MCL) is a rare B-cell lymphoma that is typically incurable with standard therapies. While the majority of cases follow an aggressive clinical course, a subset of MCL patients have indolent disease and significantly longer survival. Molecular characterization of MCLs has implicated proliferation as a strong prognostic indicator and can be used for risk stratification. Genetic features that contribute to such phenotypes in MCL are poorly understood. Here, we performed a large-scale genomic analysis using data from available published cohorts in addition to 51 exomes and 34 genomes of newly sequenced MCLs, totaling 84 exomes and 34 genomes. To confirm our findings, each of the significantly mutated genes was re-sequenced in a cohort of 212 MCL tumors. We found that MEF2B frequently harbored K23R mutations in MCL, which is distinct from the DLBCL and FL-associated hot spots described previously. We discovered three genes with roles in RNA metabolism and splicing, namely DAZAP1, EWSR1, and HNRNPH1, as frequently mutated in MCL, and further illustrate a functional role for mutations in HNRNPH1 disrupting an auto-regulatory feedback mechanism. Mutations affecting these RNA-binding proteins factors strongly implicate a role for alternative splicing in MCL pathobiology.

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