EZH2 alterations in follicular lymphoma: biological and clinical correlations

• Published in: Blood cancer journal (New York) Vol. 7; no. 4; p. e555
• Main Authors: Huet, S, Xerri, L, Tesson, B, Mareschal, S, Taix, S, Mescam-Mancini, L, Sohier, E, Carrère, M, Lazarovici, J, Casasnovas, O, Tonon, L, Boyault, S, Hayette, S, Haioun, C, Fabiani, B, Viari, A, Jardin, F, Salles, G
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21-04-2017; Springer Nature B.V; Nature Publishing Group
• Subjects: 38/91; 45; 45/23; 631/67/69; 692/308/575; 692/699/1541/1990/291/1621/1915; Adult; Aged; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Line, Tumor; Disease-Free Survival; Enhancer of Zeste Homolog 2 Protein - genetics; Female; Gene Expression Regulation, Neoplastic - genetics; Hematology; Histone-Lysine N-Methyltransferase - genetics; Humans; Life Sciences; Lymphoma, Follicular - drug therapy; Lymphoma, Follicular - genetics; Lymphoma, Follicular - pathology; Male; Methylation - drug effects; Middle Aged; Mutation - genetics; Oncology; Original; original-article; Polymorphism, Single Nucleotide - genetics; Sequence Analysis, RNA
• ISSN: 2044-5385; 2044-5385
• DOI: 10.1038/bcj.2017.32

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.