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Oquendo et al. J Transl Genet Genom 2021;5:89-111 Journal of Translational
DOI: 10.20517/jtgg.2021.04
Genetics and Genomics

Review Open Access

The (epi)genomic landscape of splenic marginal
zone lymphoma, biological implications, clinical

utility, and future questions

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Carolina Jaramillo Oquendo , Helen Parker , David Oscier , Sarah Ennis , Jane Gibson , Jonathan C.
Strefford 2
1
Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
2
Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
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Department of Haematology, Royal Bournemouth Hospital, Bournemouth BH7 7DW, UK.
Correspondence to: Prof. Jonathan C. Strefford, Cancer Sciences, Faculty of Medicine, University of Southampton, MP824
Somers Building, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK. E-mail: jcs@soton.ac.uk
How to cite this article: Oquendo CJ, Parker H, Oscier D, Ennis S, Gibson J, Strefford JC. The (epi)genomic landscape of splenic
marginal zone lymphoma, biological implications, clinical utility, and future questions. J Transl Genet Genom 2021;5:89-111.
https://dx.doi.org/10.20517/jtgg.2021.04
Received: 26 Feb 2021 First Decision: 29 Mar 2021 Revised: 6 Apr 2021 Accepted: 12 May 2021 Available online: 25 May 2021

Academic Editor: Susan L. Slager Copy Editor: Yue-Yue Zhang Production Editor: Yue-Yue Zhang

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

© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing,
adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as
long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and
indicate if changes were made.

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