Abstract

Follicular lymphoma (FL) and the GCB subtype of diffuse large B-cell lymphoma (DLBCL) derive from germinal center B cells1. Targeted resequencing studies have revealed mutations in various genes encoding proteins in the NF-κB pathway2,3 that contribute to the activated B-cell (ABC) DLBCL subtype, but thus far few GCB-specific mutations have been identified4. Here we report recurrent somatic mutations affecting the polycomb-group oncogene5 EZH2, which encodes a histone methyltransferase responsible for trimethylating Lys27 of histone H3 (H3K27). After the recent discovery of mutations in KDM6A (UTX), which encodes the histone H3K27me3 demethylase UTX, in several cancer types6, EZH2 is the second histone methyltransferase gene found to be mutated in cancer. These mutations, which result in the replacement of a single tyrosine in the SET domain of the EZH2 protein (Tyr641), occur in 21.7% of GCB DLBCLs and 7.2% of FLs and are absent from ABC DLBCLs. Our data are consistent with the notion that EZH2 proteins with mutant Tyr641 have reduced enzymatic activity in vitro.

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GenBank/EMBL/DDBJ

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Acknowledgements

This study was funded in part by grants from the National Cancer Institute Office of Cancer Genomics (see below), the National Cancer Institute of Canada (NCIC) Terry Fox Foundation New Frontiers Program Project Grant (grant no. 016003/grant type 230/project title: Biology of Cancer: Follicular Lymphoma as a Model of Cancer Progression) and Genome Canada/Genome BC Grant Competition III (project title: High Resolution Analysis of Follicular Lymphoma Genomes) to J.M.C., M.A.M., R.D.G. and D.E.H. and was supported by The Terry Fox Foundation (grant no. 019001). In addition, N.A.J. is a research fellow of the Terry Fox Foundation through an award from the NCIC (019005) and the Michael Smith Foundation for Health Research (MSFHR) (ST-PDF-01793). M.A.M. is a Terry Fox Young Investigator and a Michael Smith Senior Research Scholar. A.J.M. is supported by a Fellowship Award from The Leukemia & Lymphoma Society. R.D.M. is a Vanier Scholar (Canadian Institutes for Health Research) and is also supported by a MSFHR senior graduate fellowship. The laboratory work for this study was undertaken at the Genome Sciences Centre, British Columbia Cancer Research Centre and the Centre for Translational and Applied Genomics, a program of the Provincial Health Services Authority Laboratories. The authors thank the BC Cancer Foundation and the Lion's Club International for their support. The authors gratefully acknowledge D. Gerhard for helpful discussions. Special thanks to C. Suragh and A. Drobnies for expert project management assistance. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. NO1-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government.

Author information

Affiliations

  1. Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.

    • Ryan D Morin
    • , Tesa M Severson
    • , Andrew J Mungall
    • , Jianghong An
    • , Rodrigo Goya
    • , Jessica E Paul
    • , Obi L Griffith
    • , Richard Corbett
    • , Angela Tam
    • , Richard Varhol
    • , Duane Smailus
    • , Michelle Moksa
    • , Yongjun Zhao
    • , Allen Delaney
    • , Hong Qian
    • , Inanc Birol
    • , Jacqueline Schein
    • , Richard Moore
    • , Robert Holt
    • , Steven Jones
    • , Martin Hirst
    •  & Marco A Marra
  2. BC Cancer Agency, Vancouver, British Columbia, Canada.

    • Nathalie A Johnson
    • , Merrill Boyle
    • , Bruce W Woolcock
    • , Florian Kuchenbauer
    • , Damian Yap
    • , R Keith Humphries
    • , Sohrab Shah
    • , Joseph M Connors
    •  & Samuel Aparicio
  3. BPS Biosciences, San Diego, California, USA.

    • Henry Zhu
    • , Michelle Kimbara
    • , Pavel Shashkin
    • , Jean F Charlot
    •  & Marianna Tcherpakov
  4. Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada.

    • Doug E Horsman
    •  & Randy D Gascoyne
  5. Division of Medical Oncology, University of British Columbia, Vancouver, British Columbia, Canada.

    • Joseph M Connors
  6. Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.

    • Marco A Marra

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Contributions

M.A.M., R.D.G., D.E.H. and J.M.C. conceived of the study and led the design of the experiments. R.D.M. performed the WGSS and WTSS analysis, produced Figures 1 and 2 and, with M.A.M., wrote the manuscript. N.A.J. prepared the samples, performed sample sorting and COO analysis and contributed to the text. O.L.G. and R.D.M. analyzed gene expression data. T.M.S., A.J.M. and J.E.P. performed sequence validation experiments and visual inspection of capillary sequence data. D.S. and M.M. constructed multiplexed libraries for deep resequencing of EZH2. H.Z., M.K., P.S., J.F.C., D.Y. and M.T. conducted enzymatic assays. I.B. performed statistical analysis and contributed to the manuscript. J.A. and S.J. produced the model for EZH2 and contributed to the manuscript. M.B. and B.W.W. prepared samples and performed FACS. F.K. and R.K.H. validated expression findings in the RNA. A.D., H.Q., R.C. and S.S. performed copy number analysis. A.T., Y.Z., R.H., M.H. and R.M. produced the sequencing libraries and performed the sequencing. R.V. processed raw sequencing data. R.G. identified candidate mutations. J.S., M.H. and S.A. conceived of experiments and contributed to the text.

Competing interests

Authors H.Z., M.K., P.S., J.F.C. and M.T. are employees of BPS Bioscience. This company manufactures commercial EZH2 assay kits.

Corresponding author

Correspondence to Marco A Marra.

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DOI

https://doi.org/10.1038/ng.518

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