EZH2 alterations in follicular lymphoma: biological and clinical correlations

作者：Sarah Huet, Luc Xerri, Bruno M. Tesson, Sylvain Mareschal, Sébastien Taix, Lénaïg Mescam-Mancini, Emilie Sohier, Marjorie Carrère, Julien Lazarovici, Olivier Casasnovas, Laurie Tonon, Sandrine Boyault, Sandrine Hayette, Corinne Haïoun, Bettina Fabiani, Alain Viari, Fabrice Jardin, Gilles Salles · 发表于：Blood Cancer Journal · 年份：2017 · DOI：10.1038/bcj.2017.32 · 被引用次数：99 · 研究领域：Epigenetics and DNA Methylation、Genetic Syndromes and Imprinting、Cancer-related gene regulation

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.