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. 4–6 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. 7–9 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. We first sought to assess the frequency and impact of EZH2 mutations on the clinical outcome of FL patients. The EZH2 mutation status was revealed by bidirectional Sanger sequencing, with mutations confirmed from two independent PCR amplicons. The Y641 mutations were detected in 26 of the 221 (12%) samples examined. The mutation frequency was slightly higher than previously reported, 1 with four different types of non-synonymous mutations leading to the replacement of tyrosine at codon 641 (Figure 1a). There was no association between EZH2 mutation and overall survival or time to transformation (Figure 1b). Similar results were obtained when the patient cohort was restricted to the diagnostic samples (Supplementary Figure S1). Analysis of the series of paired FL and transformed FL (t-FL) cases revealed mutations in 9 of the 31 patients (29%). A mutation was present in both the FL and t-FL samples in six patients, was restricted to the t-FL biopsy samples in two patients and to the FL sample in a single patient. Although there appeared to be an increased frequency of EZH2 mutation in these paired analyses, there was no association between EZH2 mutation and FL transformation in our FL series