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

Splenic marginal zone lymphoma is a rare lymphoma. Loss of 7q31 and somatic mutations affecting the NOTCH2 gene 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 biologic variables. An unsupervised clustering analysis of a test series of 98 samples identified two clusters with different degrees of promoter methylation. The cluster comprising samples with higher promoter methylation (High-M) had a poorer overall survival compared to the 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 pro-survival lymphoma genes were un-methylated and over-expressed. A model based on the methylation of three genes (CACNB2, HTRA1 and KLF4) identified a poorer outcome patient subset. Exposure of SMZL cell lines to a demethylating agent caused partial reversion of the High-M phenotype and inhibition of proliferation.