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Abstract

All cancers carry somatic mutations in their genomes. A subset, known as driver mutations, confer clonal selective advantage on cancer cells and are causally implicated in oncogenesis1, and the remainder are passenger mutations. The driver mutations and mutational processes operative in breast cancer have not yet been comprehensively explored. Here we examine the genomes of 100 tumours for somatic copy number changes and mutations in the coding exons of protein-coding genes. The number of somatic mutations varied markedly between individual tumours. We found strong correlations between mutation number, age at which cancer was diagnosed and cancer histological grade, and observed multiple mutational signatures, including one present in about ten per cent of tumours characterized by numerous mutations of cytosine at TpC dinucleotides. Driver mutations were identified in several new cancer genes including AKT2, ARID1B, CASP8, CDKN1B, MAP3K1, MAP3K13, NCOR1, SMARCD1 and TBX3. Among the 100 tumours, we found driver mutations in at least 40 cancer genes and 73 different combinations of mutated cancer genes. The results highlight the substantial genetic diversity underlying this common disease.

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Change history

  • 20 June 2012

    An initial was added and an affiliation was corrected for author A.L.R.; a hyphen was added to author S.N.-Z.

Accessions

Data deposits

Genome sequence data have been deposited at the European Genome-phenome Archive under accession number EGAD00001000133. Affymetrix SNP6 data have been deposited under accession number E-MTAB-1110.

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Acknowledgements

This work was supported by the Wellcome Trust (grant reference 077012/Z/05/Z) and Breakthrough Breast Cancer. P.J.C. is personally funded through a Wellcome Trust Senior Clinical Research Fellowship (grant reference WT088340MA). P.V.L. is a postdoctoral researcher at the Research Foundation - Flanders (FWO) and is a visiting scientist at the Wellcome Trust Sanger Institute, supported by a travel grant from the FWO. I.V. is supported by a fellowship from The International Human Frontier Science Program Organization. A.-L.B.-D. and A.L. are funded by the Norwegian Research Council, The Norwegian Cancer Society, The Radium Hospital Foundation and Health Region SØ. A.V.S. was supported by an ‘Interface INSERM’ grant. J.S.R.-F. is funded in part by Breakthrough Breast Cancer and is a recipient of the 2010 CRUK Future Leaders Prize. D.E. is a Principal Research Fellow of Cancer Research UK. A.T. receives financial support from the Department of Health via the National Institute for Health Research comprehensive Biomedical Research Centre award to Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London, and from King’s College Hospital NHS Foundation Trust in conjunction with The Experimental Cancer Medicine Centre Initiative jointly funded by Cancer Research UK, the National Institute for Health Research, the Welsh Assembly Government, the HSC R&D Office for Northern Ireland and the Chief Scientist Office, Scotland. C.D. and C.S. received partial funding from the MEDIC foundation and the Fonds National de Recherche Scientifique. J.M. and J.F. are funded in part by a research grant from the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research. The INCa-Synergie facility received support from the Institut National du Cancer, the Fondation Synergie-Lyon-Cancer, the Canceropole Lyon Auverge Rhone Alpes and the Centre Leon Berard. A.C.V. is funded by The Ludwig Institute for Cancer Research. L.v.’t.V. and A. Broeks receive funding from the Dutch Genomics Initiative-Cancer Genomics Center. We also acknowledge support for sample collection, banking and processing from the Biological Resource Center of Institut Curie; the Breakthrough Breast Cancer Unit; P. Watson and the BCCA Tumour Tissue Repository; the Centre for Translational Genomics; A. Lane and P. T. Simpson; the Australian Biospecimens Network; the Breast Unit at Royal Brisbane and Women’s Hospital; the Dana-Farber/Harvard SPORE in breast cancer (reference CA089393); A. M. Sieuwerts; and the Singhealth Tissue Repository, Singapore. We are grateful also for the support of T. B. Tean, and acknowledge the input and guidance of P. Spellman and A. Ashworth.

Author information

Author notes

    • Philip J. Stephens
    •  & Patrick S. Tarpey

    These authors contributed equally to this work.

Affiliations

  1. Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK

    • Philip J. Stephens
    • , Patrick S. Tarpey
    • , Helen Davies
    • , Peter Van Loo
    • , Chris Greenman
    • , David C. Wedge
    • , Serena Nik-Zainal
    • , Sancha Martin
    • , Ignacio Varela
    • , Graham R. Bignell
    • , Lucy R. Yates
    • , Elli Papaemmanuil
    • , David Beare
    • , Adam Butler
    • , Angela Cheverton
    • , John Gamble
    • , Jonathan Hinton
    • , Mingming Jia
    • , Alagu Jayakumar
    • , David Jones
    • , Calli Latimer
    • , King Wai Lau
    • , Stuart McLaren
    • , David J. McBride
    • , Andrew Menzies
    • , Laura Mudie
    • , Keiran Raine
    • , Roland Rad
    • , Michael Spencer Chapman
    • , Jon Teague
    • , Peter J. Campbell
    • , P. Andrew Futreal
    •  & Michael R. Stratton
  2. Human Genome Laboratory, Department of Human Genetics, VIB and University of Leuven, Herestraat 49 Box 602, B-3000 Leuven, Belgium

    • Peter Van Loo
  3. School of Computing Sciences, University of East Anglia, Norwich NR4 7TJ, UK

    • Chris Greenman
  4. The Genome Analysis Centre, Norwich Research Park, Norwich NR4 7UH, UK

    • Chris Greenman
  5. Breakthrough Breast Cancer Research Unit, Research Oncology, 3rd Floor Bermondsey Wing, Guy’s Hospital Campus, Kings College London School of Medicine, London SE1 9RT, UK

    • Lucy R. Yates
    •  & Andrew Tutt
  6. Department of Clinical Oncology, Ground floor, Lambeth Wing, Guys and St Thomas’ NHS Trust, Westminster Bridge Road, London SE1 7EH, UK

    • Lucy R. Yates
  7. Centre for Cancer Genetic Epidemiology, Department of Oncology, Strangeways Research Laboratory, Cambridge CB1 8RN, UK

    • Douglas Easton
  8. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Strangeways Research Laboratory, Cambridge CB1 8RN, UK

    • Douglas Easton
  9. Department of Genetics, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, O310 Oslo, Norway

    • Anita Langerød
    •  & Anne-Lise Børresen-Dale
  10. National Genotyping Center, Institute of Biomedical Sciences, Academia Sinica, 128 Academia Road, Sec 2, Nankang, Taipei 115, Taiwan, China

    • Ming Ta Michael Lee
    •  & Chen-Yang Shen
  11. Department of General Surgery, Singapore General Hospital, 169608, Singapore

    • Benita Tan Kiat Tee
  12. NCCS-VARI Translational Research Laboratory, National Cancer Centre Singapore, 11 Hospital Drive, 169610, Singapore

    • Bernice Wong Huimin
  13. Department Experimental Therapy, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

    • Annegien Broeks
    •  & Laura van ‘t Veer
  14. The University of Queensland Centre for Clinical Research, The Royal Brisbane & Women’s Hospital, Herston, Brisbane, Queensland 4029, Australia

    • Ana Cristina Vargas
    •  & Sunil R. Lakhani
  15. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada

    • Gulisa Turashvili
    •  & Samuel A. J. R. Aparicio
  16. Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada

    • Gulisa Turashvili
    •  & Samuel A. J. R. Aparicio
  17. Department of Medical Oncology, Erasmus University Medical Center, Daniel den Hoed Cancer Center and Cancer Genomics Center, Postbus 2040, 3000 CA Rotterdam, Netherlands

    • John Martens
    •  & John Foekens
  18. Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA

    • Aquila Fatima
    • , Penelope Miron
    •  & Andrea L. Richardson
  19. Department of Oncology, University of Cambridge and Cancer Research UK Cambridge Research Institute, Li Ka Shin Centre, Cambridge CB2 0RE, UK

    • Suet-Feung Chin
    •  & Carlos Caldas
  20. Universite Lyon 1, INCa-Synergie, Centre Leon Berard, 28 rue Laennec, Lyon CEDEX 08, France

    • Gilles Thomas
    •  & Sandrine Boyault
  21. Institut Curie, Department of Tumor Biology, 26 rue d’Ulm, 75248 Paris CEDEX 05, France

    • Odette Mariani
    •  & Anne Vincent Salomon
  22. The University of Queensland School of Medicine, Herston Road, Herston, Brisbane, Queensland 4006, Australia

    • Sunil R. Lakhani
  23. Anatomical Pathology, Pathology Queensland, The Royal Brisbane and Women’s Hospital, Herston, Brisbane, Queensland 4029, Australia

    • Sunil R. Lakhani
  24. Department of Pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

    • Marc van de Vijver
  25. Breast Cancer Translational Laboratory, Université Libre de Bruxelles, Jules Bordet Institute, Boulevard de Waterloo 121, 1000 Brussels, Belgium

    • Christine Desmedt
    •  & Christos Sotiriou
  26. NIHR Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 2QQ, UK

    • Carlos Caldas
  27. The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, UK

    • Jorge S. Reis-Filho
  28. Institut Curie, INSERM Unit 830, 26 rue d’Ulm, 75248 Paris CEDEX 05, France

    • Anne Vincent Salomon
  29. K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, O318 Oslo, Norway

    • Anne-Lise Børresen-Dale
  30. Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St, Boston, Massachusetts 02115, USA

    • Andrea L. Richardson
  31. Department of Haematology, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK

    • Peter J. Campbell
  32. Department of Haematology, University of Cambridge, Hills Road, Cambridge CB2 2XY, UK

    • Peter J. Campbell
  33. Department of Breast and Endocrine Surgery, Oslo University Hospital, O424 Oslo, Norway.

    • Rolf Karesen
    •  & Ellen Schlichting
  34. Medical Faculty, University of Oslo, O424 Oslo, Norway.

    • Rolf Karesen
    • , Bjorn Naume
    •  & Torill Sauer
  35. Department of Oncology, Oslo University Hospital, O424 Oslo, Norway.

    • Bjorn Naume
    •  & Lars Ottestad
  36. Department of Pathology, Oslo University Hospital, O424 Oslo, Norway.

    • Torill Sauer

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  1. The Oslo Breast Cancer Consortium (OSBREAC)

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Contributions

P.J.S., P.S.T. and H.D. performed analysis of the sequence data, aided by S.N.Z., I.V., G.R.B., L.R.Y., E.P., D.J.M., M.S.-C. and R.R. P.V.L. performed analysis of the SNP6 data. C.G., D.C.W., K.W.L. and D.E. performed the statistical investigations. S. Martin coordinated sample acquisition and pathology review. S. McLaren coordinated sample processing. D.B., A. Butler, J.G., J.H., M.J., A.J., D.J., A.M., K.R. and J.T. performed informatics investigations. A.C., C.L. and L.M performed technical investigations. A.L., OSBREAC, M.T.M.L., C.-Y.S., B.T.K.T., B.W.H., A. Broeks, A.C.V., G. Turashvili, J.M., A.F., P.M., S.-F.C., G. Thomas, S.B., O.M., S.R.L., M.v.d.V., L.v.’t.V., J.F., C.D., C.S., A.T., C.C., J.S.R.-F., S.A.J.R.A., A.V.S., A.-L.B.-D. and A.R. contributed samples, clinical data and scientific advice. P.J.C. and P.A.F. directed the research and contributed to the manuscript. M.R.S. directed the research and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Michael R. Stratton.

Supplementary information

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https://doi.org/10.1038/nature11017

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