PT  - JOURNAL ARTICLE
AU  - Prasath Pararajalingam
AU  - Krysta M. Coyle
AU  - Sarah E. Arthur
AU  - Nicole Thomas
AU  - Miguel Alcaide
AU  - Barbara Meissner
AU  - Merrill Boyle
AU  - Bruno M. Grande
AU  - Graham Slack
AU  - Andrew J. Mungall
AU  - Randy D. Gascoyne
AU  - Christian Steidl
AU  - Joseph Connors
AU  - Diego Villa
AU  - Marco A. Marra
AU  - Nathalie Johnson
AU  - David W. Scott
AU  - Ryan D. Morin
TI  - Coding and non-coding drivers of mantle cell lymphoma identified through exome and genome sequencing
AID  - 10.1101/686956
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 686956
4099  - http://biorxiv.org/content/early/2019/07/08/686956.short
4100  - http://biorxiv.org/content/early/2019/07/08/686956.full
AB  - Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma (NHL) that is incurable with standard therapies. The genetic drivers of this cancer have not been firmly established and the features known to contribute to differences in clinical course remain limited. To extend our understanding of the biological pathways involved in this malignancy, we performed a large-scale genomic analysis of MCL using data from 51 exomes alongside previously published exome cohorts. To confirm our findings, we re-sequenced the genes identified in the exome cohort in 212 MCL tumors, each having clinical follow-up data. We confirmed the prognostic association of TP53 and NOTCH1 mutations and further nominate two additional genes, EWSR1 and MEF2B, whose mutation respectively associated with poor and good outcome. Our sequencing revealed novel recurrent mutations including a unique missense hot spot in MEF2B and a pattern of non-coding mutations surrounding a single exon of the HNRNPH1 gene. We sequenced the whole genomes of 34 MCLs to confirm the focal nature of HNRNPH1 mutations. Using RNA-seq data from 110 of these cases, we identified a functional role for recurrent non-coding HNRNPH1 mutations in disrupting an auto-regulatory feedback mechanism. Overall, we identified three novel MCL-related genes with roles in RNA trafficking or splicing, namely DAZAP1, EWSR1, and HNRNPH1. Taken together, these data strongly implicate a role for aberrant regulation of splicing in MCL pathobiology.Key pointsRNA-binding proteins with roles in regulating alternative splicing, DAZAP1, EWSR1, HNRNPH1, are frequently mutated in MCLThe majority of recurrent somatic HNRNPH1 mutations are intronic and HNRNPH1 exhibits self-regulation through alternative splicing