Gene mutations and actionable genetic lesions in mantle cell lymphoma

Ahmed, Makhdum; Zhang, Leo Yu; Nomie, Krystle; Lam, Laura; Wang, Michael

doi:10.18632/oncotarget.10716

Cited by 33 publications

(27 citation statements)

References 74 publications

(75 reference statements)

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“…Several genes have previously been implicated as recurrent targets of SSM in MCL 9-11,38 though many of these candidate drivers have been inconsistent between individual studies 39 . This can be attributed to a combination of genetic heterogeneity and limited cohort sizes.…”

Section: Somatic Mutation Landscape and Recurrently Mutated Genesmentioning

confidence: 99%

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

Pararajalingam¹,

Coyle²,

Arthur³

et al. 2019

Preprint

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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.

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Section: Somatic Mutation Landscape and Recurrently Mutated Genesmentioning

confidence: 99%

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

Pararajalingam¹,

Coyle²,

Arthur³

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…The genomic landscape of most aggressive lymphomas, including the majority of MCL cases, shows tremendous variation (12,13). In MCL, frequent mutations in particular genes are reported in only a fraction of patients, thus making it difficult to target genetic lesions.…”

Section: Targeting Genetic Lesions In MCLmentioning

confidence: 99%

“…Somatic mutations, which are nonheritable genetic variations, are particularly common in MCL cells (12,13,15,16). MCL somatic mutations are associated with the activation of various B cell pathways-a phenomenon that can be explored to identify therapeutic targets (17).…”

Section: Somatic Mutations In MCLmentioning

confidence: 99%

“…Advancements have been made in high-throughput and affordable sequencing, genome-editing technologies, DNA sequencing, and RNA sequencing; studies that have examined the mutational landscape through targeted sequencing appear to have identified recurring mutations with these methods. There are several genes, namely, ATM, TP53, MLL2, TRAF2, CARD11, and BIRC3 (12,13,(15)(16)(17), which are reported to be frequently mutated in primary MCL cells, with the ATM mutation found in nearly 50% of patients with MCL (15). Large-scale genomic studies are using the next-generation sequencing platform to describe the frequency of these mutations, mutational burden, copy number variations, and clinical importance of the somatic variants.…”

Section: Somatic Mutations In MCLmentioning

confidence: 99%

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Interrogating B cell signaling pathways: A quest for novel therapies for mantle cell lymphoma

et al. 2019

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Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma that is largely chemoresistant. Ibrutinib, a drug that inhibits Bruton’s tyrosine kinase (BTK), has improved the overall survival of patients with MCL; however, resistance to ibrutinib has emerged as a decisive, negative factor in the prognosis of MCL. Adopting a more patient-centric therapeutic approach that incorporates applied genomics and interrogation of B cell signaling pathways may offer an alternative route to reach durable remission in patients with MCL. Although targeting genetic variants in MCL is not yet feasible in the clinical setting, the identification and targeting of increasingly active B cell signaling pathways may be a viable therapeutic strategy that may improve patient outcomes. Genome-editing tools and sequencing platforms could play dominant roles in patient-centric approaches of treatment in the future, potentially improving clinical outcomes for patients with MCL.

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“…Indeed it seems that CCND1 is not the only gene affected in MCL and recurrent mutations are found in other genes belonging to different pathways and cellular processes e.g. cell cycle (ATM), epigenetic regulation (MLL2 and 3), NF-kB pathway (BIRC2 and 3) (reviewed in (Ahmed et al, 2016)). Some MCL cases exist lacking CCND1 overexpression but carrying secondary alteration as SOX11overexpression (Jares et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Large-scale nuclear remodeling and transcriptional deregulation occur on both derivative chromosomes after Mantle Cell Lymphoma chromosomal translocation

Sall

Pichugin

Iarovaia

et al. 2019

Preprint

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Recurrent chromosomal translocations are found in many blood and solid cancers. Balanced translocations, frequent in lymphoid malignancies, lead to the formation of two aberrant derivative (der) chromosomes. This event often leads to overexpression of an oncogene. In many cases, the expression of an oncogene is not enough to produce a malignant phenotype; however, most part of the studies focus on the events involving the chromosome where the oncogene is located, but rarely the other der chromosome where other oncogenic alterations may potentially arise. Mantle cell lymphoma (MCL), an aggressive B-cell non-Hodgkin lymphoma, is a perfect example of this. In 85% of the cases, it is characterized by the translocation t(11;14), which leads to the overexpression of cyclin D1 (CCND1) gene which results juxtaposed to the immunoglobulin heavy chain (IGH) gene on the der14 chromosome.This feature alone is not sufficient to induce oncogenesis. Here we focused on the der11 chromosome. We demonstrated that expression of 88 genes located in a 15mb region close to the translocation breakpoint on the der11 was deregulated both in the GRANTA-519 MCL cell line and in B-cells from MCL patients. We found that a large segment of der11containing deregulated genes was relocated from its normal position in the nuclear periphery towards the center of the nucleus in close proximity to the nucleolus where the abundant nucleolar protein nucleolin binds a subset of genes located close to the breakpoint and activates their expression. This finding allowed to identify new potential oncogenes involved in MCL and the mechanisms of their upregulation.

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Gene mutations and actionable genetic lesions in mantle cell lymphoma

Cited by 33 publications

References 74 publications

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

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

Interrogating B cell signaling pathways: A quest for novel therapies for mantle cell lymphoma

Large-scale nuclear remodeling and transcriptional deregulation occur on both derivative chromosomes after Mantle Cell Lymphoma chromosomal translocation

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