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Lymphoma

BCL2 mutations in diffuse large B-cell lymphoma

Leukemia volume 26, pages 1383–1390 (2012)Cite this article

Abstract

BCL2 is deregulated in diffuse large B-cell lymphoma (DLBCL) by the t(14;18) translocation, gene amplification and/or nuclear factor-κB signaling. RNA-seq data have recently shown that BCL2 is the most highly mutated gene in germinal center B-cell (GCB) DLBCL. We have sequenced BCL2 in 298 primary DLBCL biopsies, 131 additional non-Hodgkin lymphoma biopsies, 24 DLBCL cell lines and 51 germline DNAs. We found frequent BCL2 mutations in follicular lymphoma (FL) and GCB DLBCL, but low levels of BCL2 mutations in activated B-cell DLBCL, mantle cell lymphoma, small lymphocytic leukemia and peripheral T-cell lymphoma. We found no BCL2 mutations in GC centroblasts. Many mutations were non-synonymous; they were preferentially located in the flexible loop domain, with few in BCL2-homology domains. An elevated transition/transversions ratio supports that the mutations result from somatic hypermutation. BCL2 translocations correlate with, and are likely important in acquisition of, additional BCL2 mutations in GCB DLBCL and FL. DLBCL mutations were not independently associated with survival. Although previous studies of BCL2 mutations in FL have reported mutations to result in pseudo-negative BCL2 protein expression, we find this rare in de-novo DLBCL.

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Acknowledgements

We thank Bruce Woolcock for laboratory work assistance; Martin Hirst, Yongjun Zhao, Angela Tam, Richard Moore and Thomas Zeng for assistance with RNA-seq data; Martin Krzywinski for assistance with the design of Figure 2; and Douglas E Horsman for cytogenetics input. JMS was supported by the Lionel McLeod Award by the Alberta Heritage Foundation for Medical Research and by the Canadian Institutes for Health Research (CIHR). JMS was a PhD candidate at the University of British Columbia and this work was submitted in partial fulfillment of the requirement for the PhD. RDM was a Vanier Scholar of the CIHR and holds a Senior Graduate Studentship from the Michael Smith Foundation for Health Research (MSFHR). DWS and KT were supported by the Terry Fox Foundation Strategic Health Research Training Program in Cancer Research at Canadian Institutes of Health Research (Grant No. TGT-53912). ARB-W was a Senior Scholar of the MSFHR. RDG and JMC are supported by a Program Project Grant for the Terry Fox Foundation (019001). This project was funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E.

Author contributions

JMS and NAJ performed the experiments and wrote the paper. RDM performed the analysis of whole-genome libraries. All authors participated in study design and edited the manuscript.

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Author notes

  1. J M Schuetz and N A Johnson: These authors contributed equally to this work.

  2. A R Brooks-Wilson and R D Gascoyne: These authors contributed equally to this work.

Authors and Affiliations

  1. Canada's Michael Smith Genome Sciences Center, BC Cancer Agency, University of British Columbia, Vancouver, British Columbia, Canada

    J M Schuetz, R D Morin, M A Marra & A R Brooks-Wilson

  2. Division of Hematology and Oncology, Jewish General Hospital, Montreal, Québec, Canada

    N A Johnson

  3. Department of Pathology, Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada

    D W Scott, K Tan, S Ben-Nierah, M Boyle, G W Slack & R D Gascoyne

  4. Division of Medical Oncology, Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada

    J M Connors

  5. Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada

    A R Brooks-Wilson

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  1. J M Schuetz
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Correspondence to R D Gascoyne.

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Schuetz, J., Johnson, N., Morin, R. et al. BCL2 mutations in diffuse large B-cell lymphoma. Leukemia 26, 1383–1390 (2012). https://doi.org/10.1038/leu.2011.378

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