Landscape of somatic mutations in 560 breast cancer whole-genome sequences

  • Nature volume 534, pages 4754 (02 June 2016)
  • doi:10.1038/nature17676
  • Download Citation


We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.

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Data deposits

Raw data have been submitted to the European-Genome Phenome Archive under the overarching accession number EGAS00001001178 (please see Supplementary Notes for breakdown by data type). Somatic variants have been deposited at the International Cancer Genome Consortium Data Portal (


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This work has been funded through the ICGC Breast Cancer Working group by the Breast Cancer Somatic Genetics Study (BASIS), a European research project funded by the European Community’s Seventh Framework Programme (FP7/2010-2014) under the grant agreement number 242006; the Triple Negative project funded by the Wellcome Trust (grant reference 077012/Z/05/Z) and the HER2+ project funded by Institut National du Cancer (INCa) in France (grant numbers 226-2009, 02-2011, 41-2012, 144-2008, 06-2012). The ICGC Asian Breast Cancer Project was funded through a grant of the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A111218-SC01). Personally funded by grants above: F.G.R.-G., S.M., K.R., S.M. were funded by BASIS. Recruitment was performed under the auspices of the ICGC breast cancer projects run by the UK, France and Korea. For contributions towards instruments, specimens and collections: Tayside Tissue Bank (funded by CRUK, University of Dundee, Chief Scientist Office & Breast Cancer Campaign), Asan Bio-Resource Center of the Korea Biobank Network, Seoul, South Korea, OSBREAC consortium, The Icelandic Centre for Research (RANNIS), The Swedish Cancer Society and the Swedish Research Council, and Fondation Jean Dausset-Centre d’Etudes du polymorphisme humain. Icelandic Cancer Registry, The Brisbane Breast Bank (The University of Queensland, The Royal Brisbane and Women’s Hospital and QIMR Berghofer), Breast Cancer Tissue and Data Bank at KCL and NIHR Biomedical Research Centre at Guy’s and St Thomas’s Hospitals. Breakthrough Breast Cancer and Cancer Research UK Experimental Cancer Medicine Centre at KCL. For pathology review: The Mouse Genome Project and Department of Pathology, Cambridge University Hospitals NHS Foundation Trust for microscopes. A. Richardson, A. Ehinger, A. Vincent-Salomon, C. Van Deurzen, C. Purdie, D. Larsimont, D. Giri, D. Grabau, E. Provenzano, G. MacGrogan, G. Van den Eynden, I. Treilleux, J. E. Brock, J. Jacquemier, J. Reis-Filho, L. Arnould, L. Jones, M. van de Vijver, Ø. Garred, R. Salgado, S. Pinder, S. R. Lakhani, T. Sauer, V. Barbashina. Illumina UK Ltd for input on optimization of sequencing throughout this project. Wellcome Trust Sanger Institute Sequencing Core Facility, Core IT Facility and Cancer Genome Project Core IT team and Cancer Genome Project Core Laboratory team for general support. Personal funding: S.N.-Z. is a Wellcome Beit Fellow and personally funded by a Wellcome Trust Intermediate Fellowship (WT100183MA). L.B.A. is supported through a J. Robert Oppenheimer Fellowship at Los Alamos National Laboratory. A.L.R. is partially supported by the Dana-Farber/Harvard Cancer Center SPORE in Breast Cancer (NIH/NCI 5 P50 CA168504-02). D.G. was supported by the EU-FP7-SUPPRESSTEM project. A.S. was supported by Cancer Genomics Netherlands through a grant from the Netherlands Organisation of Scientific research (NWO). M.S. was supported by the EU-FP7-DDR response project. C.S. and C.D. are supported by a grant from the Breast Cancer Research Foundation. E.B. was funded by EMBL. C.S. is funded by FNRS (Fonds National de la Recherche Scientifique). S.J.J. is supported by Leading Foreign Research Institute Recruitment Program through the National Research Foundation of Republic Korea (NRF 2011-0030105). G.K. is supported by National Research Foundation of Korea (NRF) grants funded by the Korean government (NRF 2015R1A2A1A10052578). J.F. received funding from an ERC Advanced grant (no. 322737). For general contribution and administrative support: Fondation Synergie Lyon Cancer in France. J. G. Jonasson, Department of Pathology, University Hospital & Faculty of Medicine, University of Iceland. K. Ferguson, Tissue Bank Manager, Brisbane Breast Bank and The Breast Unit, The Royal Brisbane and Women's Hospital, Brisbane, Australia. The Oslo Breast Cancer Consortium of Norway (OSBREAC). Angelo Paradiso, IRCCS Istituto Tumori “Giovanni Paolo II”, Bari Italy. A. Vines for administratively supporting to identifying the samples, organizing the bank, and sending out the samples. M. Schlooz-Vries, J. Tol, H. van Laarhoven, F. Sweep, P. Bult in Nijmegen for contributions in Nijmegen. This research used resources provided by the Los Alamos National Laboratory Institutional Computing Program, which is supported by the US Department of Energy National Nuclear Security Administration under contract no. DE-AC52-06NA25396. Research performed at Los Alamos National Laboratory was carried out under the auspices of the National Nuclear Security Administration of the United States Department of Energy. N. Miller (in memoriam) for her contribution in setting up the clinical database. Finally, we would like to acknowledge all members of the ICGC Breast Cancer Working Group and ICGC Asian Breast Cancer Project.

Author information


  1. Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK

    • Serena Nik-Zainal
    • , Helen Davies
    • , Manasa Ramakrishna
    • , Dominik Glodzik
    • , Xueqing Zou
    • , Inigo Martincorena
    • , Ludmil B. Alexandrov
    • , Sancha Martin
    • , David C. Wedge
    • , Peter Van Loo
    • , Young Seok Ju
    • , Adam Butler
    • , Serge Dronov
    • , Moritz Gerstung
    • , David R. Jones
    • , Yilong Li
    • , Stuart McLaren
    • , Andrew Menzies
    • , Ville Mustonen
    • , Sarah O’Meara
    • , Keiran Raine
    • , Kamna Ramakrishnan
    • , Rebecca Shepherd
    • , Lucy Stebbings
    • , Jon Teague
    • , Lucy Yates
    • , P. Andrew Futreal
    • , Peter J. Campbell
    •  & Michael R. Stratton
  2. East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 9NB, UK

    • Serena Nik-Zainal
  3. Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund SE-223 81, Sweden

    • Johan Staaf
    • , Markus Ringnér
    •  & Åke Borg
  4. Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, Los Alamos, NM 87545, New Mexico, USA

    • Ludmil B. Alexandrov
  5. Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA

    • Ludmil B. Alexandrov
  6. Department of Human Genetics, University of Leuven, B-3000 Leuven, Belgium

    • Peter Van Loo
  7. Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam 3015CN, The Netherlands

    • Marcel Smid
    • , John A. Foekens
    • , F. Germán Rodríguez-González
    • , Anieta M. Sieuwerts
    •  & John W. M. Martens
  8. Radboud University, Department of Molecular Biology, Faculty of Science, 6525GA Nijmegen, The Netherlands

    • Arie B. Brinkman
    •  & Hendrik G. Stunnenberg
  9. European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK

    • Sandro Morganella
    •  & Ewan Birney
  10. Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo 0310, Norway

    • Miriam R. Aure
    • , Anita Langerød
    •  & Anne-Lise Børresen-Dale
  11. K. G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo 0310, Norway

    • Miriam R. Aure
    • , Ole Christian Lingjærde
    • , Anita Langerød
    •  & Anne-Lise Børresen-Dale
  12. Department of Computer Science, University of Oslo, Oslo, Norway

    • Ole Christian Lingjærde
  13. Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center, Incheon, South Korea

    • Sung-Min Ahn
  14. Translational Research Lab, Centre Léon Bérard, 28, rue Laënnec, 69373 Lyon Cedex 08, France

    • Sandrine Boyault
  15. Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA

    • Jane E. Brock
    •  & Andrea L. Richardson
  16. The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands

    • Annegien Broeks
    • , Laura van’t Veer
    •  & Jos Jonkers
  17. Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Bd de Waterloo 121, B-1000 Brussels, Belgium

    • Christine Desmedt
    •  & Christos Sotiriou
  18. Translational Cancer Research Unit, Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium

    • Luc Dirix
    • , Gert G. Van den Eynden
    • , Peter Vermeulen
    •  & Steven Van Laere
  19. Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA

    • Aquila Fatima
    •  & Andrea L. Richardson
  20. Department of Pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

    • Gerrit K. J. Hooijer
    •  & Marc J. van de Vijver
  21. Department of Pathology, Asan Medical Center, College of Medicine, Ulsan University, Ulsan, South Korea

    • Se Jin Jang
    •  & Hee Jin Lee
  22. Department of Pathology, College of Medicine, Hanyang University, Seoul 133-791, South Korea

    • Hyung-Yong Kim
    •  & Gu Kong
  23. Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA

    • Tari A. King
  24. Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard., Houston, Texas 77030, USA

    • Savitri Krishnamurthy
    •  & Naoto T. Ueno
  25. Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul, South Korea

    • Jeong-Yeon Lee
  26. Institut National du Cancer, Research Division, Clinical Research Department, 52 avenue Morizet, 92513 Boulogne-Billancourt, France

    • Iris Pauporté
  27. University Hospital of Minjoz, INSERM UMR 1098, Bd Fleming, Besançon 25000, France

    • Xavier Pivot
  28. Pathology Department, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK

    • Colin A. Purdie
    •  & Alastair M. Thompson
  29. Oncologie Sénologie, ICM Institut Régional du Cancer, Montpellier, France

    • Gilles Romieu
  30. The University of Queensland, UQ Centre for Clinical Research and School of Medicine, Brisbane, Queensland 4029, Australia

    • Peter T. Simpson
    •  & Sunil R. Lakhani
  31. Cancer Research Laboratory, Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland

    • Olafur A. Stefansson
    •  & Jorunn E. Eyfjord
  32. IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, Italy

    • Stefania Tommasi
  33. Department of Pathology, Centre Léon Bérard, 28 rue Laënnec, 69373 Lyon Cédex 08, France

    • Isabelle Treilleux
  34. Department of Pathology, GZA Hospitals Sint-Augustinus, Antwerp, Belgium

    • Gert G. Van den Eynden
    •  & Peter Vermeulen
  35. Institut Curie, Paris Sciences Lettres University, Department of Pathology and INSERM U934, 26 rue d’Ulm, 75248 Paris Cedex 05, France

    • Anne Vincent-Salomon
  36. Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK

    • Carlos Caldas
  37. Breast Cancer Now Research Unit, King’s College London, London SE1 9RT, UK

    • Andrew Tutt
  38. Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London SW3 6JB, UK

    • Andrew Tutt
  39. Department of Clinical Science, University of Bergen, 5020 Bergen, Norway

    • Stian Knappskog
  40. Department of Oncology, Haukeland University Hospital, 5021 Bergen, Norway

    • Stian Knappskog
  41. National Cancer Centre Singapore, 11 Hospital Drive, 169610, Singapore

    • Benita Kiat Tee Tan
  42. Singapore General Hospital, Outram Road, 169608, Singapore

    • Benita Kiat Tee Tan
  43. Equipe Erable, INRIA Grenoble-Rhône-Alpes, 655, Avenue de l’Europe, 38330 Montbonnot-Saint Martin, France

    • Alain Viari
  44. Synergie Lyon Cancer, Centre Léon Bérard, 28 rue Laënnec, Lyon Cedex 08, France

    • Alain Viari
    •  & Gilles Thomas
  45. Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, Texas 77230, USA

    • P. Andrew Futreal
  46. Department of Radiation Oncology, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands

    • Paul N. Span
  47. Pathology Queensland, The Royal Brisbane and Women’s Hospital, Brisbane, Queensland 4029, Australia

    • Sunil R. Lakhani
  48. Department of Breast Surgical Oncology, University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Houston, Texas 77030, USA

    • Alastair M. Thompson


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S.N.-Z., M.R.S. designed the study, analysed data and wrote the manuscript. H.D., J.S., M. Ramakrishna, D.G., X.Z. performed curation of data and contributed towards genomic and copy number analyses. M.S., A.B.B., M.R.A., O.C.L., A.L., M. Ringner, contributed towards curation and analysis of non-genomic data (transcriptomic, miRNA, methylation). I.M., L.B.A., D.C.W., P.V.L., S. Morganella, Y.S.J., contributed towards specialist analyses. G.T., G.K., A.L.R., A-L.B.-D., J.W.M.M., M.J.v.d.V., H.G.S., E.B., A. Borg., A.V., P.A.F., P.J.C., designed the study, drove the consortium and provided samples. S.Martin was the project coordinator. S.McL., S.O.M., K.R., contributed operationally. S.-M.A., S.B., J.E.B., A.Brooks., C.D., L.D., A.F., J.A.F., G.K.J.H., S.J.J., H.-Y.K., T.A.K., S.K., H.J.L., J.-Y.L., I.P., X.P., C.A.P., F.G.R.-G., G.R., A.M.S., P.T.S., O.A.S., S.T., I.T., G.G.V.d.E., P.V., A.V.-S., L.Y., C.C., L.v.V., A.T., S.K., B.K.T.T., J.J., N.t.U., C.S., P.N.S., S.V.L., S.R.L., J.E.E., A.M.T contributed pathology assessment and/or samples. A. Butler., S.D., M.G., D.R.J., Y.L., A.M., V.M., K.R., R.S., L.S., J.T. contributed IT processing and management expertise. All authors discussed the results and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Serena Nik-Zainal or Alain Viari or Gu Kong or Michael R. Stratton.

Extended data

Supplementary information

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    Supplementary Information

    This file contains some acknowledgements and the EGA accession numbers.

Zip files

  1. 1.

    Supplementary Tables

    This file zipped contains Supplementary Tables 1-21.


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