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

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.