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 and KLF2 genes are the commonest genomic aberrations. Epigenetic changes can be pharmacologically reverted; therefore, identification of groups of patients with specific epigenomic alterations...

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Bibliographic Details
Published in:Blood 2015-03, Vol.125 (12), p.1922-1931
Main Authors: Arribas, Alberto J., Rinaldi, Andrea, Mensah, Afua A., Kwee, Ivo, Cascione, Luciano, Robles, Eloy F., Martinez-Climent, Jose A., Oscier, David, Arcaini, Luca, Baldini, Luca, Marasca, Roberto, Thieblemont, Catherine, Briere, Josette, Forconi, Francesco, Zamò, Alberto, Bonifacio, Massimiliano, Mollejo, Manuela, Facchetti, Fabio, Dirnhofer, Stephan, Ponzoni, Maurilio, Bhagat, Govind, Piris, Miguel A., Gaidano, Gianluca, Zucca, Emanuele, Rossi, Davide, Bertoni, Francesco
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Cell Proliferation
Cell Transformation, Neoplastic
Cluster Analysis
DNA Methylation
DNA Mutational Analysis
Female
Gene Expression Profiling
Humans
Kaplan-Meier Estimate
Lymphoid Neoplasia
Lymphoma, B-Cell, Marginal Zone - diagnosis
Lymphoma, B-Cell, Marginal Zone - genetics
Lymphoma, B-Cell, Marginal Zone - mortality
Male
Middle Aged
Mutation
Phenotype
Prognosis
Promoter Regions, Genetic
Splenic Neoplasms - diagnosis
Splenic Neoplasms - genetics
Splenic Neoplasms - mortality
Treatment Outcome
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Summary: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. •Methylation profiling identifies subgroups of SMZL with distinct biological features.•Demethylating agents can reverse some of the adverse epigenetic alterations.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2014-08-596247