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

Alberto J. Arribas, Andrea Rinaldi, Afua A. Mensah, Ivo Kwee, Luciano Cascione, Eloy F. Robles, Jose A. Martinez-Climent, David Oscier, Luca Arcaini, Luca Baldini, Roberto Marasca, Catherine Thieblemont, Josette Briere, Francesco Forconi, Alberto Zamò, Massimiliano Bonifacio, Manuela Mollejo, Fabio Facchetti, Stephan Dirnhofer, Maurilio PonzoniGovind Bhagat, Miguel A. Piris, Gianluca Gaidano, Emanuele Zucca, Davide Rossi, Francesco Bertoni

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1922-1931
Number of pages10
JournalBlood
Volume125
Issue number12
DOIs
Publication statusPublished - Mar 19 2015

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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