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

Author

Listed:
  • Serena Nik-Zainal

    (Wellcome Trust Sanger Institute, Hinxton
    East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust)

  • Helen Davies

    (Wellcome Trust Sanger Institute, Hinxton)

  • Johan Staaf

    (Lund University)

  • Manasa Ramakrishna

    (Wellcome Trust Sanger Institute, Hinxton)

  • Dominik Glodzik

    (Wellcome Trust Sanger Institute, Hinxton)

  • Xueqing Zou

    (Wellcome Trust Sanger Institute, Hinxton)

  • Inigo Martincorena

    (Wellcome Trust Sanger Institute, Hinxton)

  • Ludmil B. Alexandrov

    (Wellcome Trust Sanger Institute, Hinxton
    Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory
    Center for Nonlinear Studies, Los Alamos National Laboratory)

  • Sancha Martin

    (Wellcome Trust Sanger Institute, Hinxton)

  • David C. Wedge

    (Wellcome Trust Sanger Institute, Hinxton)

  • Peter Van Loo

    (Wellcome Trust Sanger Institute, Hinxton
    University of Leuven)

  • Young Seok Ju

    (Wellcome Trust Sanger Institute, Hinxton)

  • Marcel Smid

    (Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center)

  • Arie B. Brinkman

    (Radboud University, Faculty of Science)

  • Sandro Morganella

    (European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus)

  • Miriam R. Aure

    (Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital
    K. G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo)

  • Ole Christian Lingjærde

    (K. G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo
    University of Oslo)

  • Anita Langerød

    (Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital
    K. G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo)

  • Markus Ringnér

    (Lund University)

  • Sung-Min Ahn

    (Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center)

  • Sandrine Boyault

    (Translational Research Lab, Centre Léon Bérard, 28, rue Laënnec)

  • Jane E. Brock

    (Brigham and Women’s Hospital)

  • Annegien Broeks

    (The Netherlands Cancer Institute)

  • Adam Butler

    (Wellcome Trust Sanger Institute, Hinxton)

  • Christine Desmedt

    (Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet)

  • Luc Dirix

    (Translational Cancer Research Unit, Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp)

  • Serge Dronov

    (Wellcome Trust Sanger Institute, Hinxton)

  • Aquila Fatima

    (Dana-Farber Cancer Institute)

  • John A. Foekens

    (Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center)

  • Moritz Gerstung

    (Wellcome Trust Sanger Institute, Hinxton)

  • Gerrit K. J. Hooijer

    (Academic Medical Center)

  • Se Jin Jang

    (Asan Medical Center, College of Medicine, Ulsan University)

  • David R. Jones

    (Wellcome Trust Sanger Institute, Hinxton)

  • Hyung-Yong Kim

    (College of Medicine, Hanyang University)

  • Tari A. King

    (Memorial Sloan Kettering Cancer Center)

  • Savitri Krishnamurthy

    (Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard.)

  • Hee Jin Lee

    (Asan Medical Center, College of Medicine, Ulsan University)

  • Jeong-Yeon Lee

    (Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University)

  • Yilong Li

    (Wellcome Trust Sanger Institute, Hinxton)

  • Stuart McLaren

    (Wellcome Trust Sanger Institute, Hinxton)

  • Andrew Menzies

    (Wellcome Trust Sanger Institute, Hinxton)

  • Ville Mustonen

    (Wellcome Trust Sanger Institute, Hinxton)

  • Sarah O’Meara

    (Wellcome Trust Sanger Institute, Hinxton)

  • Iris Pauporté

    (Institut National du Cancer)

  • Xavier Pivot

    (University Hospital of Minjoz, INSERM UMR 1098, Bd Fleming)

  • Colin A. Purdie

    (Ninewells Hospital and Medical School)

  • Keiran Raine

    (Wellcome Trust Sanger Institute, Hinxton)

  • Kamna Ramakrishnan

    (Wellcome Trust Sanger Institute, Hinxton)

  • F. Germán Rodríguez-González

    (Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center)

  • Gilles Romieu

    (Oncologie Sénologie, ICM Institut Régional du Cancer)

  • Anieta M. Sieuwerts

    (Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center)

  • Peter T. Simpson

    (The University of Queensland, UQ Centre for Clinical Research and School of Medicine)

  • Rebecca Shepherd

    (Wellcome Trust Sanger Institute, Hinxton)

  • Lucy Stebbings

    (Wellcome Trust Sanger Institute, Hinxton)

  • Olafur A. Stefansson

    (Cancer Research Laboratory, Faculty of Medicine, University of Iceland)

  • Jon Teague

    (Wellcome Trust Sanger Institute, Hinxton)

  • Stefania Tommasi

    (IRCCS Istituto Tumori “Giovanni Paolo II”)

  • Isabelle Treilleux

    (Centre Léon Bérard, 28 rue Laënnec)

  • Gert G. Van den Eynden

    (Translational Cancer Research Unit, Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp
    GZA Hospitals Sint-Augustinus)

  • Peter Vermeulen

    (Translational Cancer Research Unit, Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp
    GZA Hospitals Sint-Augustinus)

  • Anne Vincent-Salomon

    (Institut Curie, Paris Sciences Lettres University, 26 rue d’Ulm)

  • Lucy Yates

    (Wellcome Trust Sanger Institute, Hinxton)

  • Carlos Caldas

    (Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way)

  • Laura van’t Veer

    (The Netherlands Cancer Institute)

  • Andrew Tutt

    (Breast Cancer Now Research Unit, King’s College London
    Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research)

  • Stian Knappskog

    (University of Bergen
    Haukeland University Hospital)

  • Benita Kiat Tee Tan

    (National Cancer Centre Singapore
    Singapore General Hospital)

  • Jos Jonkers

    (The Netherlands Cancer Institute)

  • Åke Borg

    (Lund University)

  • Naoto T. Ueno

    (Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard.)

  • Christos Sotiriou

    (Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet)

  • Alain Viari

    (Equipe Erable, INRIA Grenoble-Rhône-Alpes
    Synergie Lyon Cancer, Centre Léon Bérard, 28 rue Laënnec)

  • P. Andrew Futreal

    (Wellcome Trust Sanger Institute, Hinxton
    UT MD Anderson Cancer Center)

  • Peter J. Campbell

    (Wellcome Trust Sanger Institute, Hinxton)

  • Paul N. Span

    (Radboud University Medical Center)

  • Steven Van Laere

    (Translational Cancer Research Unit, Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp)

  • Sunil R. Lakhani

    (The University of Queensland, UQ Centre for Clinical Research and School of Medicine
    Pathology Queensland, The Royal Brisbane and Women’s Hospital)

  • Jorunn E. Eyfjord

    (Cancer Research Laboratory, Faculty of Medicine, University of Iceland)

  • Alastair M. Thompson

    (Ninewells Hospital and Medical School
    University of Texas MD Anderson Cancer Center)

  • Ewan Birney

    (European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus)

  • Hendrik G. Stunnenberg

    (Radboud University, Faculty of Science)

  • Marc J. van de Vijver

    (Academic Medical Center)

  • John W. M. Martens

    (Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center)

  • Anne-Lise Børresen-Dale

    (Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital
    K. G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo)

  • Andrea L. Richardson

    (Brigham and Women’s Hospital
    Dana-Farber Cancer Institute)

  • Gu Kong

    (College of Medicine, Hanyang University)

  • Gilles Thomas

    (Synergie Lyon Cancer, Centre Léon Bérard, 28 rue Laënnec)

  • Michael R. Stratton

    (Wellcome Trust Sanger Institute, Hinxton)

Abstract

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.

Suggested Citation

  • Serena Nik-Zainal & Helen Davies & Johan Staaf & Manasa Ramakrishna & Dominik Glodzik & Xueqing Zou & Inigo Martincorena & Ludmil B. Alexandrov & Sancha Martin & David C. Wedge & Peter Van Loo & Young, 2016. "Landscape of somatic mutations in 560 breast cancer whole-genome sequences," Nature, Nature, vol. 534(7605), pages 47-54, June.
    • Handle: RePEc:nat:nature:v:534:y:2016:i:7605:d:10.1038_nature17676
    DOI: 10.1038/nature17676
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