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EZH2 Y641 mutations in follicular lymphoma

Leukemia volume 25, pages 726–729 (2011)Cite this article

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The introduction of next-generation sequencing technologies is leading to the discovery of many novel mutational targets in haematological malignancies. Morin et al.1 recently reported somatic heterozygous mutations within the catalytic SET domain of the histone methyltransferase EZH2 in about 7% of follicular lymphoma (FL) cases. The mutations occurred exclusively at codon 641 (Y641), leading to a marked reduction in the enzymatic activity of EZH2 in vitro.1 The gene encodes the catalytic subunit of the polycomb repressive complex 2 (PRC2) that mediates trimethylation of lysine 27 on histone H3 (H3K27me3), an epigenetic mark associated with transcriptional silencing. The PRC2/EZH2 complex binds to a specific set of target genes in germinal centre (GC) centroblasts, suggesting a GC-specific EZH2 regulatory programme in normal and malignant B cells.2 Indeed, DNA-methylation profiling studies in FL by our group and others have shown that PRC2 gene targets in stem cells are significantly overrepresented among the hypermethylated genes in these tumours, linking these two epigenetic mechanisms in FL.3 The spectrum of cancers with EZH2 mutation is also increasing, with mutations in myeloid disorders leading to reduced or complete loss of H3K27me3 expression consistent with a tumour suppressor role for EZH2.4, 5, 6 Deregulation of the EZH2–H3K27me3 pathway may also occur by other mechanisms, with over-expression of EZH2 associated with poor outcome in a range of solid tumours.7, 8, 9

In this study, we set out to determine the prevalence and the prognostic value of EZH2 Y641 variants in a large cohort of patients with FL, and the relationship between mutation and EZH2 and H3K27me3 expression. Lymph node samples from 221 patients with FL were available from the tissue archive at St Barts and London Hospital (London Research Ethical Committee (05/Q0605/140)). Of these, 56 samples were obtained at diagnosis, with 165 samples taken at relapse. The major clinical characteristics of these patients are summarized in Table 1. We also tested 31 paired pre- and post-transformation lymph node biopsy samples in order to trace the patterns of EZH2 mutation over time.

Table 1 Characteristics of the FL samples analysed
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Acknowledgements

This research was funded by the Partner Fellowship (2009/01) awarded by the European Hematology Association, CRUK programme grant C1574/A6806 and by the Leukemia Lymphoma Research UK grant.

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Authors and Affiliations

  1. Centre of Haemato-Oncology, Institute of Cancer, Barts and the London School of Medicine, Queen Mary University of London, London, UK

    C Bödör, C O'Riain, D Wrench, J Matthews, S Iyengar, H Tayyib, M Calaminici, A Clear, S Iqbal, S Montoto, A T Lister, J G Gribben & J Fitzgibbon

  2. 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary

    C Bödör & A Matolcsy

  3. DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany

    H Quentmeier & H G Drexler

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  1. C Bödör
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Correspondence to C Bödör.

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Bödör, C., O'Riain, C., Wrench, D. et al. EZH2 Y641 mutations in follicular lymphoma. Leukemia 25, 726–729 (2011). https://doi.org/10.1038/leu.2010.311

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