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Blood Cancer J. 2017 Apr 21;7(4):e555. doi: 10.1038/bcj.2017.32.

EZH2 alterations in follicular lymphoma: biological and clinical correlations.

Author information

1
Hospices Civils de Lyon, Laboratoire d'Hématologie, Pierre Bénite, France.
2
INSERM1052, CNRS 5286, Université Claude Bernard, Faculté de Médecine Lyon Sud Charles Mérieux, Université de Lyon, Pierre Bénite, France.
3
Department of Bio-Pathology, Hematology, and Tumor Immunology, Institut Paoli-Calmettes and Aix-Marseille University, Marseille, France.
4
Institut Carnot CALYM, Pierre Bénite, France.
5
Department of Hematology, Henri Becquerel Comprehensive Cancer Center and Normandie Univ, UNIROUEN, Inserm U1245, Rouen, France.
6
Synergie Lyon Cancer, Bio-Informatics Platform, Centre Léon Bérard, Lyon, France.
7
Département de Recherche Translationnelle et de l'Innovation, Génomique des Cancers, Centre Léon Bérard, Lyon, France.
8
Département d'Hématologie, Gustave-Roussy, Université Paris-Seclay, Villejuif, France.
9
Department of Hematology and INSERM UMR1231, Hôpital Le Bocage, University Hospital of Dijon, Dijon, France.
10
Lymphoid Malignancies Unit, Hôpital Henri Mondor, University Hospital, APHP, Créteil, France.
11
Department of Pathology, Centre Hospitalier Saint Antoine, Paris, France.
12
Hospices Civils de Lyon, Service d'Hématologie Clinique Pavillon 1 F, Centre Hospitalier Lyon Sud, Pierre Bénite, France.

Abstract

The histone methyltransferase EZH2 has an essential role in the development of follicular lymphoma (FL). Recurrent gain-of-function mutations in EZH2 have been described in 25% of FL patients and induce aberrant methylation of histone H3 lysine 27 (H3K27). We evaluated the role of EZH2 genomic gains in FL biology. Using RNA sequencing, Sanger sequencing and SNP-arrays, the mutation status, copy-number and gene-expression profiles of EZH2 were assessed in a cohort of 159 FL patients from the PRIMA trial. Immunohistochemical (IHC) EZH2 expression (n=55) and H3K27 methylation (n=63) profiles were also evaluated. In total, 37% of patients (59/159) harbored an alteration in the EZH2 gene (mutation n=46, gain n=23). Both types of alterations were associated with highly similar transcriptional changes, with increased proliferation programs. An H3K27me3/me2 IHC score fully distinguished mutated from wild-type samples, showing its applicability as surrogate for EZH2 mutation analysis. However, this score did not predict the presence of gains at the EZH2 locus. The presence of an EZH2 genetic alteration was an independent factor associated with a longer progression-free survival (hazard ratio 0.58, 95% confidence interval 0.36-0.93, P=0.025). We propose that the copy-number status of EZH2 should also be considered when evaluating patient stratification and selecting patients for EZH2 inhibitor-targeted therapies.

PMID:
28430172
PMCID:
PMC5436075
DOI:
10.1038/bcj.2017.32
[Indexed for MEDLINE]
Free PMC Article

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