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The (epi)genomic landscape of splenic marginal zone lymphoma: biological implications, clinical utility, and future questions

The (epi)genomic landscape of splenic marginal zone lymphoma: biological implications, clinical utility, and future questions
The (epi)genomic landscape of splenic marginal zone lymphoma: biological implications, clinical utility, and future questions
Splenic marginal zone lymphoma (SMZL) is an indolent B-cell lymphoma comprising less than 2% of lymphoid neoplasms. Approximately 70% of patients have a progressive disease requiring treatment and up to 30% of patients relapse or transform to diffuse large B-cell lymphoma. Whilst research over the last decade has transformed our understanding of many B-cell tumours, it is only beginning to shed light on the molecular pathogenesis of SMZL. Expansive immunogenetic investigations have shown biases in the immunoglobulin gene repertoire with distinct patterns of somatic hypermutation, suggesting a pathogenic role for antigen selection. In parallel cytogenetic studies have found a number of recurrent chromosomal lesions, in particular a deletion of the long arm of chromosome 7, though causative genes have not been identified. Our understanding of the mutational landscape of SMZL is built on a limited number of index cases, but has highlighted recurrent mutations in KLF2, NOTCH2 and TP53, and a spectrum of genes that cluster within biological pathways of importance in B-cell differentiation. While preliminary DNA methylation profiling has shown epigenetically distinct patient sub-groups, including a group defined by elevated expression of polycomb repressor complex 2 components. This review will provide an overview of our current understanding of the molecular basis of SMZL, and how this information impacts patient outcomes. Furthermore, we will outline; (1) the knowledge gaps that still exist; (2) a potential future research direction; and (3) how a detailed molecular understanding of the disease will ultimately provide patients with improved management and treatment choices.
Jaramillo Oquendo, Carolina
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Parker, Helen
33e0cd81-d45f-49bc-9539-09345d79d895
Oscier, David
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Ennis, Sarah
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Gibson, Jane
855033a6-38f3-4853-8f60-d7d4561226ae
Strefford, Jonathan
3782b392-f080-42bf-bdca-8aa5d6ca532f
Jaramillo Oquendo, Carolina
41b94f4b-3f6d-4d9d-9251-a5a1597a5766
Parker, Helen
33e0cd81-d45f-49bc-9539-09345d79d895
Oscier, David
2e7f0cc1-93e2-441e-857d-7314efae08ec
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9
Gibson, Jane
855033a6-38f3-4853-8f60-d7d4561226ae
Strefford, Jonathan
3782b392-f080-42bf-bdca-8aa5d6ca532f

Jaramillo Oquendo, Carolina, Parker, Helen, Oscier, David, Ennis, Sarah, Gibson, Jane and Strefford, Jonathan (2021) The (epi)genomic landscape of splenic marginal zone lymphoma: biological implications, clinical utility, and future questions. Journal of Translational Genetics and Genomics. (doi:10.20517/jtgg.2021.04).

Record type: Review

Abstract

Splenic marginal zone lymphoma (SMZL) is an indolent B-cell lymphoma comprising less than 2% of lymphoid neoplasms. Approximately 70% of patients have a progressive disease requiring treatment and up to 30% of patients relapse or transform to diffuse large B-cell lymphoma. Whilst research over the last decade has transformed our understanding of many B-cell tumours, it is only beginning to shed light on the molecular pathogenesis of SMZL. Expansive immunogenetic investigations have shown biases in the immunoglobulin gene repertoire with distinct patterns of somatic hypermutation, suggesting a pathogenic role for antigen selection. In parallel cytogenetic studies have found a number of recurrent chromosomal lesions, in particular a deletion of the long arm of chromosome 7, though causative genes have not been identified. Our understanding of the mutational landscape of SMZL is built on a limited number of index cases, but has highlighted recurrent mutations in KLF2, NOTCH2 and TP53, and a spectrum of genes that cluster within biological pathways of importance in B-cell differentiation. While preliminary DNA methylation profiling has shown epigenetically distinct patient sub-groups, including a group defined by elevated expression of polycomb repressor complex 2 components. This review will provide an overview of our current understanding of the molecular basis of SMZL, and how this information impacts patient outcomes. Furthermore, we will outline; (1) the knowledge gaps that still exist; (2) a potential future research direction; and (3) how a detailed molecular understanding of the disease will ultimately provide patients with improved management and treatment choices.

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JTGG-Jaramillo-Oquendo - Accepted Manuscript
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Accepted/In Press date: 12 May 2021
e-pub ahead of print date: 25 May 2021

Identifiers

Local EPrints ID: 449431
URI: http://eprints.soton.ac.uk/id/eprint/449431
PURE UUID: 1a27245c-3671-4742-9a1a-adbdcf9ca16e
ORCID for Helen Parker: ORCID iD orcid.org/0000-0001-8308-9781
ORCID for Sarah Ennis: ORCID iD orcid.org/0000-0003-2648-0869
ORCID for Jane Gibson: ORCID iD orcid.org/0000-0002-0973-8285
ORCID for Jonathan Strefford: ORCID iD orcid.org/0000-0002-0972-2881

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Date deposited: 28 May 2021 16:31
Last modified: 29 May 2021 01:39

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Contributors

Author: Carolina Jaramillo Oquendo
Author: Helen Parker ORCID iD
Author: David Oscier
Author: Sarah Ennis ORCID iD
Author: Jane Gibson ORCID iD

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