Coding and non-coding drivers of mantle cell lymphoma identified through exome and genome sequencing

Abstract

Key points• RNA-binding proteins with roles in regulating alternative splicing, DAZAP1, EWSR1, HNRNPH1, are frequently mutated in MCL • The majority of recurrent somatic HNRNPH1 mutations are intronic and HNRNPH1 exhibits self-regulation through alternative splicing AbstractMantle 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.

Genetic mutations and features of mantle cell lymphoma: a systematic review and meta-analysis

“…Additional articles reporting mutations in MCL patients were published after our inclusion period for the systematic review. 64,[68][69][70][71] These articles describe prevalent mutations similar to those reported in our analysis, including ATM, TP53, NOTCH1, and CCND1.…”

Early relapse identifies MCL patients with inferior survival after intensive or less intensive frontline therapy

“…Ongoing study is needed to further define biologic MCL risk factors including genetic and epigenetic alterations associated with early POD in order to provide better prognostication at diagnosis and inform selection of frontline treatment. A growing body of evidence has established TP53 mutations as one important biologic risk factor in MCL predictive of poor response to CIT and early mortality 15,[32][33][34] , and the lack of data regarding TP53 mutational status is a limitation of the current study. In addition, the impact of TP53 mutations on response to salvage therapy and/or novel agents is not well described.…”

Progress in molecular feature of smoldering mantle cell lymphoma

“…Interestingly, NOTCH2 mutation is a substitute for NOTCH1 mutation [84]. However, NOTCH1 was not identified as an independent prognostic factor in a multivariate model with TP53 mutations [46]. In conclusion, 9.5% of MCL patients present NOTCH1/2 mutations, which can be used to identify a subset of tumors with more aggressive biological and clinical features, including those with blastoid/pleomorphic morphology.…”

“…1). The altered splicing of HNRNPH1 was related to inferior outcomes in MCL patients [46]. All patients with WHSC1, MLL2 and UBR5 mutations responded to therapy.…”

“…Some studies have indicated that the higher the MCL risk group, the higher the percentage of patients with > 50% TP53 expression, and the expression of TP53 is related to the outcome of MCL independent of the MIPI and Ki-67 level [14,45]. However, some studies have suggested that stratifying patients by proliferation to separate them into low-, intermediate-and high-risk groups is more effective than stratifying them by any single driver mutation [45,46]. Interestingly, Lin et al showed no significant difference in prognosis between patients with and without TP53 alterations who received reduced-intensity or nonmyeloablative allogeneic hematopoietic cell transplantation, providing a beneficial treatment modality for these high-risk patients for the first time [47].…”