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The CCND1 c.870G>A polymorphism is a risk factor for t(11;14)(q13;q32) multiple myeloma

Nature Genetics volume 45, pages 522–525 (2013)Cite this article

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Abstract

A number of specific chromosomal abnormalities define the subgroups of multiple myeloma. In a meta-analysis of two genome-wide association studies of multiple myeloma including a total of 1,661 affected individuals, we investigated risk for developing a specific tumor karyotype. The t(11;14)(q13;q32) translocation in which CCND1 is placed under the control of the immunoglobulin heavy chain enhancer was strongly associated with the CCND1 c.870G>A polymorphism (P = 7.96 × 10−11). These results provide a model in which a constitutive genetic factor is associated with risk of a specific chromosomal translocation.

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Figure 1: Regional plot of association results and recombination rates around the CCND1 locus on chromosome 11q13.

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Acknowledgements

We are grateful to all the subjects and investigators at the individual centers for their participation. V.J. Forster is acknowledged for sample preparation. We also thank the staff of the CTRU (Clinical Trials Research Unit) University of Leeds and the NCRI (National Cancer Research Institute) Haematology Clinical Studies Group. In the UK, funding was provided by Myeloma UK, Leukaemia and Lymphoma Research (LLR 10021), Cancer Research UK (C1298/A8362, supported by the Bobby Moore Fund) and the National Health Service (NHS) via the Biological Research Centre of the National Institute for Health Research at the Royal Marsden Hospital NHS Trust. Leukaemia and Lymphoma Research provided funding for the Newcastle Myeloma Study (LLR 11006). In Germany, funding was provided by Dietmar-Hopp-Stiftung Walldorf, University Hospital Heidelberg and the German Cancer Aid. The HNR study was funded by the Heinz-Nixdorf Foundation (chairman M. Nixdorf) and the German Federal Ministry of Education and Research (BMBF).

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Author notes

  1. Niels Weinhold, David C Johnson and Daniel Chubb: These authors contributed equally to this work.

  2. Hartmut Goldschmidt, Richard S Houlston, Gareth J Morgan and Kari Hemminki: These authors jointly directed this work.

Authors and Affiliations

  1. Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany

    Niels Weinhold, Dirk Hose, Mathias Witzens-Harig, Kai Neben & Hartmut Goldschmidt

  2. Division of Molecular Pathology, Haemato-Oncology Research Unit, Institute of Cancer Research, Sutton, UK

    David C Johnson, Brian A Walker, Faith E Davies, Martin F Kaiser, Ni L Li & Gareth J Morgan

  3. Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, UK

    Daniel Chubb, Fay J Hosking, Peter Broderick, Yussanne P Ma, Sara E Dobbins & Richard S Houlston

  4. German Cancer Research Center, Heidelberg, Germany

    Bowang Chen, Asta Försti & Kari Hemminki

  5. Center for Primary Health Care Research, Lund University, Malmo, Sweden

    Asta Försti & Kari Hemminki

  6. National Centre for Tumour Diseases, Heidelberg, Germany

    Dirk Hose & Hartmut Goldschmidt

  7. Leeds Institute of Molecular Medicine, Section of Clinical Trials Research, University of Leeds, Leeds, UK

    Walter A Gregory

  8. Royal Victoria Infirmary, Newcastle upon Tyne, UK

    Graham H Jackson

  9. Institute of Human Genetics, University of Bonn, Bonn, Germany

    Per Hoffmann, Markus M Nöthen & Thomas W Mühleisen

  10. German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany

    Markus M Nöthen

  11. Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University of Duisburg–Essen, Essen, Germany

    Lewin Eisele

  12. Cytogenetics Group, Wessex Regional Cytogenetic Laboratory, Salisbury, UK

    Fiona M Ross

  13. Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany

    Anna Jauch

Authors
  1. Niels Weinhold
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  2. David C Johnson
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Contributions

K.H., H.G., G.J.M. and R.S.H. designed the study. R.S.H. and G.J.M. obtained financial support in the UK, and K.H. and H.G. obtained financial support in Germany. R.S.H. and K.H. drafted the manuscript with contributions from G.J.M., D.C.J. and N.W. D.C., F.J.H., B.C., D.C.J., Y.P.M., S.E.D. and N.W. performed statistical and bioinformatics analyses. P.B. coordinated UK laboratory analyses. D.C.J. managed and prepared DNA samples for Myeloma IX and Myeloma XI Case Studies and performed expression analyses. H.G., K.N., N.W. and D.H. coordinated and managed German DNA samples. M.W.-H. and N.W. managed and prepared MCL samples. L.E. managed the HNR samples. P.H., T.W.M. and M.M.N. performed and coordinated genotyping of the German controls. K.H. and A.F. coordinated genotyping, performed by P.H. and M.M.N. D.C.J., M.F.K., N.L.L. and B.A.W. performed UK expression analyses. F.M.R. performed UK FISH analyses, and A.J. performed German FISH analyses. G.J.M., F.E.D., W.A.G. and G.H.J. performed ascertainment and collection of UK case samples. All authors contributed to the final version of the manuscript.

Corresponding authors

Correspondence to Richard S Houlston or Kari Hemminki.

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The authors declare no competing financial interests.

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Weinhold, N., Johnson, D., Chubb, D. et al. The CCND1 c.870G>A polymorphism is a risk factor for t(11;14)(q13;q32) multiple myeloma. Nat Genet 45, 522–525 (2013). https://doi.org/10.1038/ng.2583

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