TY - JOUR
T1 - DNA methylation profiling identifies two splenic marginal zone lymphoma subgroups with different clinical and genetic features
AU - Arribas, Alberto J.
AU - Rinaldi, Andrea
AU - Mensah, Afua A.
AU - Kwee, Ivo
AU - Cascione, Luciano
AU - Robles, Eloy F.
AU - Martinez-Climent, Jose A.
AU - Oscier, David
AU - Arcaini, Luca
AU - Baldini, Luca
AU - Marasca, Roberto
AU - Thieblemont, Catherine
AU - Briere, Josette
AU - Forconi, Francesco
AU - Zamò, Alberto
AU - Bonifacio, Massimiliano
AU - Mollejo, Manuela
AU - Facchetti, Fabio
AU - Dirnhofer, Stephan
AU - Ponzoni, Maurilio
AU - Bhagat, Govind
AU - Piris, Miguel A.
AU - Gaidano, Gianluca
AU - Zucca, Emanuele
AU - Rossi, Davide
AU - Bertoni, Francesco
PY - 2015/3/19
Y1 - 2015/3/19
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2014-08-596247
DO - 10.1182/blood-2014-08-596247
M3 - Article
C2 - 25612624
AN - SCOPUS:84925357071
VL - 125
SP - 1922
EP - 1931
JO - Blood
JF - Blood
SN - 0006-4971
IS - 12
ER -