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

Abstract

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 that 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 and 34 genomes alongside previously published exome cohorts. To confirm our findings, we re-sequenced the genes identified in the exome cohort in 191 MCL tumors, each having clinical follow-up data. We confirmed the prognostic association of TP53 and NOTCH1 mutations. Our sequencing revealed novel recurrent non-coding mutations surrounding a single exon of the HNRNPH1 gene. In RNA-seq data from 103 of these cases, MCL tumors with these mutations had a distinct imbalance of HNRNPH1 isoforms. This altered splicing of HNRNPH1 was associated with inferior outcomes in MCL and showed a significant increase in protein expression by immunohistochemistry. We describe a functional role for these recurrent non-coding mutations in disrupting an auto-regulatory feedback mechanism, thereby deregulating HNRNPH1 protein expression. Taken together, these data strongly implicate a role for aberrant regulation of mRNA processing in MCL pathobiology.

Targeted genomic investigations in a population-based cohort of mantle cell lymphoma reveal novel clinically relevant targets

“…Additionally, there is considerable variability in which genes are affected in each individual patient (Table S5). These circumstances made it less feasible to identify driver genes in our MCL cohort, although drivers appeared mutated at a similar rate as reported previously [5,6,18]. However, when resorting to the CGI, we identified 64/75 patients (84%) that had mutations in either one established driver gene variant in cancer or a predicted driver mutation by OncodriveMUT (Table S6), which correspond to 138/382 identified variants.…”

“…The frequency of patients with mutated CCND1 was lower than previously reported. Studies that reported higher number of CCND1 mutations analyzed a large proportion of peripherial blood samples and had a much higher number of cases classified as high-risk MIPI than our study (60-91% vs. 45%, respectively) [6,18]. We also found that NSD2 was mutated at a lower frequently than expected [13].…”

“…The genetic landscape of MCL has been investigated in previous studies, although the total number of sequenced samples remains low. To our knowledge, previous larger targeting panel/global sequencing studies (studies with more than 50 studied genes) [4][5][6]17,18,[20][21][22] include only approximately 300 de novo MCL patients in total. Thus, our data on 77 patients is a significant addition to the general knowledge base of the frequency of genetic alterations in MCL.…”

Recent advances in upper gastrointestinal lymphomas: molecular updates and diagnostic implications

“…Mutations in TP53, SMARCA4, CELSR3, CCND1 and KMT2D have been found to negatively affect the response to venetoclax-based therapies. [109][110][111] The median survival is 3-5 years, and the majority of cases remain incurable, with multiple relapses. Besides standard chemotherapy, treatment options currently comprise many new drugs such as ibrutinib, lenalidomide, bortezomib, temsirolimus, and venetoclax.…”

“…The genomic landscape of MCL is heterogeneous, and comprises mutations in genes involved in DNA damage response ( ATM and TP53 ) and Notch signalling ( NOTCH1 and NOTCH2 ), and in genes affecting RNA metabolism and splicing ( EWSR1 , DAZAP1 , and HNRNPH1 ). Mutations in TP53 , SMARCA4 , CELSR3 , CCND1 and KMT2D have been found to negatively affect the response to venetoclax‐based therapies 109–111 …”