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Genome-wide association study identifies a common variant in RAD51B associated with male breast cancer risk

Nature Genetics volume 44, pages 1182–1184 (2012)Cite this article

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Abstract

We conducted a genome-wide association study of male breast cancer comprising 823 cases and 2,795 controls of European ancestry, with validation in independent sample sets totaling 438 cases and 474 controls. A SNP in RAD51B at 14q24.1 was significantly associated with male breast cancer risk (P = 3.02 × 10−13; odds ratio (OR) = 1.57). We also refine association at 16q12.1 to a SNP within TOX3 (P = 3.87 × 10−15; OR = 1.50).

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Figure 1: Association and recombination plots for loci associated with male breast cancer risk.

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Acknowledgements

We thank the men who participated in the study. For ICR sample collection, we are grateful to B. Smith, D. Hogben, R. McCann, J. Melia, S. Squires, M. Snigorska, J. Micic and K. Sibley for administrative help and advice; to the research nurses A. Butlin, M. Pelerin, J. Wood and T. Gardener for collection of blood samples and questionnaire data from participants; to D. Thomas and her team from the Breakthrough Generations Study for coordinating collection of controls; and to the cancer registries of England and Wales for providing information on eligible participants. The Study of Epidemiology and Risk Factors in Cancer Heredity (SEARCH) thanks the SEARCH team. We wish to thank H. Thorne, E. Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics and the Clinical Follow Up Study (funded from 2001–2009 by the Australian National Health & Medical Research Council (NHMRC) and currently by the National Breast Cancer Foundation and Cancer Australia, 628333) for their contributions to this resource and the many families who contribute to kConFab. We thank G. Wilhoite for preparing the US samples for this study. We thank A. Jukkola-Vuorinen, V. Kataja and P. Auvinen, as well as S. Hallamies and S. Ranta, for their contributions to the Finnish Male Breast Cancer Study. We thank J. Forteza, M. Fraga, C. Celeiro and the staff of the Department of Pathology of CHUS Santiago and A. Carracedo and C.M. Redondo for their contributions to the Spanish study. Finally, we thank the consultants who cared for the study participants for their advice and help. The Breakthrough Male Breast Cancer Study was approved by the South Eastern Research Ethics Committee. Participants gave informed consent for all aspects of the study.

This work was supported by Breakthrough Breast Cancer, Movember and the Institute of Cancer Research who acknowledge National Health Service (NHS) funding to the National Institute for Health Research (NIHR) Biomedical Research Centre. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics is funded by Wellcome Trust grant 090532/Z/09/Z and UK Medical Research Council (MRC) Hub grant G0900747 91070. This work made use of data and samples generated by the 1958 British Birth Cohort under grant G0000934 from the UK MRC and grant 068545/Z/02 from the Wellcome Trust. The Finnish Male Breast Cancer Study acknowledges funding from the Finnish Breast Cancer Group, the Finnish Oncology Association and the Salonoja Foundation. L.O. acknowledges funding from the Italian Association for Cancer Research (AIRC, IG 8713). D.P. acknowledges funding from the Istituto Toscano Tumori, Florence, Italy. SEARCH is funded by a grant from Cancer Research UK (C490/A10124) and is supported by the University of Cambridge NIHR Biomedical Research Centre. A.M.D. has been funded by Cancer Research UK grant CA8197/A10865 and by the Joseph Mitchell Fund. D.T.B. acknowledges funding by Cancer Research UK (Programme Award C588/A10589). M.G.-D. and J.E.C. acknowledge the support of the Department of Pathology of the CHUS Santiago Hospital, the Galician Foundation of Genomic Medicine and the Program Grupos Emergentes, Cancer Genetics Unit of CHUVI, Instituto de Salud Carlos III. H.O. and I.H. acknowledge funding from the Swedish Cancer Society and The Swedish Medical Research Council. The collection of samples and epidemiological data for the US cases was supported by US ARMY Grant DAMD-17-96-I-6266 and US National Institutes of Health (NIH) grant R01CA74415. S.L.N. was partially supported by the Morris and Horowitz Families Endowed Professorship at the City of Hope.

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Authors and Affiliations

  1. The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK

    Nick Orr, Alina Lemnrau, Olivia Fletcher, Katarzyna Tomczyk, Nichola Johnson, Christopher J Lord, Costas Mitsopoulos, Marketa Zvelebil, Montserrat Garcia-Closas & Alan Ashworth

  2. Division of Breast Cancer Research, The Institute of Cancer Research, Sutton, UK

    Nick Orr, Alina Lemnrau, Rosie Cooke, Olivia Fletcher, Katarzyna Tomczyk, Michael Jones, Nichola Johnson, Christopher J Lord, Costas Mitsopoulos, Marketa Zvelebil, Montserrat Garcia-Closas, Alan Ashworth & Anthony J Swerdlow

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

    Rosie Cooke, Michael Jones, Richard S Houlston, Montserrat Garcia-Closas & Anthony J Swerdlow

  4. Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University of Belfast, Belfast, UK

    Simon S McDade

  5. High-Throughput Genomics Group, Wellcome Trust Centre for Human Genetics, Oxford, UK

    Gemma Buck & Christine Blancher

  6. Familial Cancer Clinic, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia

    Alison H Trainer & Paul A James

  7. Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark

    Stig E Bojesen

  8. Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark

    Susanne Bokmand

  9. Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

    Heli Nevanlinna

  10. Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland

    Johanna Mattson

  11. The Susanne Levy Gertner Oncogenetics Unit, Sheba Medical Centre, Tel Aviv, Israel

    Eitan Friedman & Yael Laitman

  12. The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel

    Eitan Friedman & Yael Laitman

  13. Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute (ISPO), Florence, Italy

    Domenico Palli, Giovanna Masala & Ines Zanna

  14. Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy

    Laura Ottini & Giuseppe Giannini

  15. Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands

    Antoinette Hollestelle

  16. Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands

    Ans M W van den Ouweland

  17. Department of Molecular Diagnostics, Institute of Oncology Ljubljana, Ljubljana, Slovenia

    Srdjan Novaković

  18. Institute of Oncology Ljubljana, Cancer Genetics Clinic, Epidemiology and Cancer Registry, Ljubljana, Slovenia

    Mateja Krajc

  19. Galician Foundation of Genomic Medicine, Complexo Hospitalario Universitario Santiago (CHUS), Servicio Galego de Saude (SERGAS), Instituto de Investigación Sanitaria de Santiago de Compostela, Santiago de Compostela, Spain

    Manuela Gago-Dominguez

  20. Genetic Oncology Unit, Complexo Hospitalario Universitario de Vigo (CHUVI), SERGAS, Vigo, Spain

    Jose Esteban Castelao

  21. Department of Oncology, Lund University, Lund, Sweden

    Håkan Olsson & Ingrid Hedenfalk

  22. Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK

    Douglas F Easton & Paul D P Pharoah

  23. Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK

    Douglas F Easton, Paul D P Pharoah & Alison M Dunning

  24. Division of Cancer Studies and Pathology, Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK

    D Timothy Bishop

  25. Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California, USA

    Susan L Neuhausen & Linda Steele

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  1. Nick Orr
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Consortia

KConFab Consortium

Contributions

A.A. and A.J.S. conceived the Breakthrough Breast Cancer Male Breast Cancer Study and obtained financial support. N.O. and A.J.S. designed the GWAS. N.O. drafted the manuscript with substantial input from O.F., M.J., C.J.L., R.S.H., M.G.-C., A.A. and A.J.S. N.O., R.C., S.S.M., C.M. and M.Z. performed statistical and bioinformatics analyses. K.T. managed sample handling and DNA extraction. A.L., N.J., G.B. and C.B. performed genotyping. A.H.T. and P.A.J. coordinated sample collection at the Peter MacCallum Cancer Centre; S.E.B. and S.B. coordinated sample collection at Copenhagen University Hospital; H.N. and J.M. coordinated sample collection for the Finnish Male Breast Cancer Study; E.F. and Y.L. coordinate sample collection at Sheba Medical Centre and the Sackler School of Medicine; D.P., G.M. and I.Z. coordinated sample collection at ISPO (Cancer Research and Prevention Institute); L.O. and G.G. coordinated sample collection at Sapienza University of Rome; A.H. and A.M.W.v.d.O. coordinated sample collection at Erasmus University Medical Center; S.N. and M.K. coordinated sample collection at the Institute of Oncology Ljubljana; M.G.-D. and J.E.C. coordinated sample collection in Galicia, Spain; H.O. and I.H. coordinated sample collection at Lund University; D.F.E., P.D.P.P. and A.M.D. coordinated sample collection for the SEARCH/Cambridge studies; D.T.B. coordinated sample collection at the Leeds Institute of Molecular Medicine; and S.L.N. and L.S. coordinated collection of US samples. All authors contributed to the final manuscript.

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Correspondence to Nick Orr.

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The authors declare no competing financial interests.

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A list of members and affiliations is provided in the Supplementary Note.

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Supplementary Figures 1–7, Supplementary Tables 1–7, Supplementary Methods and Supplementary Note (PDF 1917 kb)

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Orr, N., Lemnrau, A., Cooke, R. et al. Genome-wide association study identifies a common variant in RAD51B associated with male breast cancer risk. Nat Genet 44, 1182–1184 (2012). https://doi.org/10.1038/ng.2417

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