DNA methylation profiling identifies two splenic marginal zone lymphoma subgroups with different clinical and genetic features

Abstract

Key Points• Methylation profiling identifies subgroups of SMZL with distinct biological features.• Demethylating agents can reverse some of the adverse epigenetic alterations.Splenic marginal zone lymphoma is a rare lymphoma. Loss of 7q31 and somatic mutations affecting the NOTCH2 and KLF2 genes are the commonest genomic aberrations. Epigenetic changes can be pharmacologically reverted; therefore, identification of groups of patients with specific epigenomic alterations might have therapeutic relevance. Here we integrated genome-wide DNA-promoter methylation profiling with gene expression profiling, and clinical and biological variables. An unsupervised clustering analysis of a test series of 98 samples identified 2 clusters with different degrees of promoter methylation. The cluster comprising samples with higher-promoter methylation (High-M) had a poorer overall survival compared with the lower (Low-M) cluster. The prognostic relevance of the High-M phenotype was confirmed in an independent validation set of 36 patients. In the whole series, the High-M phenotype was associated with IGHV1-02 usage, mutations of NOTCH2 gene, 7q31-32 loss, and histologic transformation. In the High-M set, a number of tumor-suppressor genes were methylated and repressed. PRC2 subunit genes and several prosurvival lymphoma genes were unmethylated and overexpressed. A model based on the methylation of 3 genes (CACNB2, HTRA1, KLF4) identified a poorer-outcome patient subset. Exposure of splenic marginal zone lymphoma cell lines to a demethylating agent caused partial reversion of the High-M phenotype and inhibition of proliferation. (Blood. 2015;125(12):1922-1931

High-Grade Transformation in a Splenic Marginal Zone Lymphoma with a Cerebral Manifestation

“…For SMZLs, the frequency of the histologic transformation of varies from 5% to 19% [4–7,12,13]. A recent retrospective study reported an incidence rate of 5% for histological transformation in a large series of 85 SMZL patients, whose median follow-up time was 4.8 years [6].…”

Murine Models of Splenic Marginal Zone Lymphoma: A Role for Cav1?

“…Many studies have been done in hopes of finding exactly which genes and pathways are altered in SMZL, therefore serving as potential targets on the development of SMZL murine models. A summary of these studies can be found in Table 1 (8, 9, 11, 13–15, 17–25). Although many genes (most notably NOTCH2, KLF2, KLF4, and BIRC3) have been reported as mutated in SMZL, we suggest that the 7q deletion is of primary importance, as it is possible this deletion serves as a marker for disease progression and may even be a causative event, rather than a pro-survival function as was previously speculated (9).…”

“…In a genome-wide DNA-promoter methylation profiling study by Arribas et al, two main clusters were distinguished based on the degree of promoter DNA methylation (15). This high-M cluster not only had an inferior outcome and showed high risk for histologic transformation to DLBCL but suggests that DNA hypermethylation could act together with 7q31-32 deletion, NOTCH2 mutation, and IGHV1-02, to determine a distinct genetic and epigenetic subgroup of SMZL (11).…”

“…These three malignancies have major commonalities (27–30), including some shared surface markers, shared pathways for disease progression (15), and hypothesized infectious disease drivers, including HCV (Figure 1). …”

DNA methylation in lymphoma: an opportunity?

“…1 In this edition of Blood, Arribas et al show that DNA methylation profiling identifies 2 subtypes of splenic marginal zone lymphoma with different clinical and genetic features. 2 These findings provide an opportunity to better understand the biology of marginal zone lymphoma and optimize therapy by using demethylating agents to reverse the high-methylation phenotype and thereby target malignant B cells. S plenic marginal zone lymphoma is an uncommon B-cell malignancy representing ;8% of all non-Hodgkin lymphomas.…”