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Signatures of mutational processes in human cancer

Author

Listed:
  • Ludmil B. Alexandrov

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

  • Serena Nik-Zainal

    (Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
    Box 134, Addenbrooke’s Hospital NHS Trust, Hills Road, Cambridge CB2 0QQ, UK.)

  • David C. Wedge

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

  • Samuel A. J. R. Aparicio

    (Molecular Oncology, Michael Smith Genome Sciences Centre, BC Cancer Agency, 675 West 10th Avenue, Vancouver V5Z 1L3, Canada.
    Centre for Translational and Applied Genomics, Michael Smith Genome Sciences Centre, BC Cancer Agency, 675 West 10th Avenue, Vancouver V5Z 1L3, Canada.
    University of British Columbia, G227-2211 Wesbrook Mall, British Columbia, Vancouver V6T 2B5, Canada.)

  • Sam Behjati

    (Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
    University of Cambridge, Hills Road, Cambridge CB2 2XY, UK.)

  • Andrew V. Biankin

    (Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
    West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G4 0SF, UK.
    The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.
    Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia.)

  • Graham R. Bignell

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

  • Niccolò Bolli

    (Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
    Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK.
    University of Cambridge, Cambridge CB2 2XY, UK.)

  • Ake Borg

    (Lund University, SE-221 85 Lund, Sweden.)

  • Anne-Lise Børresen-Dale

    (Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway.
    The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, N-0310 Oslo, Norway.)

  • Sandrine Boyault

    (Plateforme de Bioinformatique Synergie Lyon Cancer, Centre Léon Bérard, 28 rue Laennec, 69373 Lyon Cedex 08, France.)

  • Birgit Burkhardt

    (University Children’s Hospital, 48149 Münster, Germany.
    University Children’s Hospital, 35392 Giessen, Germany.)

  • Adam P. Butler

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

  • Carlos Caldas

    (Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK.)

  • Helen R. Davies

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

  • Christine Desmedt

    (Breast Cancer Translational Res Lab -BCTL, Université Libre de Bruxelles—Institut Jules Bordet, Boulevard de Waterloo, 125, B-1000 Brussels, Belgium.)

  • Roland Eils

    (German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.)

  • Jórunn Erla Eyfjörd

    (Cancer Research Laboratory, Faculty of Medicine, Biomedical Centre, University of Iceland, 101 Reykjavik, Iceland.)

  • John A. Foekens

    (Erasmus MC Cancer Institute, 3015 CE Rotterdam, The Netherlands.)

  • Mel Greaves

    (Institute of Cancer Research, London SM2 5NG, UK.)

  • Fumie Hosoda

    (National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.)

  • Barbara Hutter

    (German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.)

  • Tomislav Ilicic

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

  • Sandrine Imbeaud

    (INSERM, UMR-674, Génomique Fonctionnelle des Tumeurs Solides, Institut Universitaire d’Hematologie (IUH), 75475 Paris, France.
    Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, 75006 Paris, France.)

  • Marcin Imielinski

    (The Broad Institute of MIT and Harvard)

  • Natalie Jäger

    (German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.)

  • David T. W. Jones

    (German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.)

  • David Jones

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

  • Stian Knappskog

    (Section of Oncology, University of Bergen, 5020 Bergen, Norway.
    Haukeland University Hospital, 5021 Bergen, Norway.)

  • Marcel Kool

    (German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.)

  • Sunil R. Lakhani

    (The University of Queensland Centre for Clinical Research, School of Medicine and Pathology Queensland, The Royal Brisbane & Women’s Hospital, Herston 4029, Brisbane, Queensland, Australia.)

  • Carlos López-Otín

    (IUOPA-Universidad de Oviedo, 33006 Oviedo, Spain.)

  • Sancha Martin

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

  • Nikhil C. Munshi

    (Jerome Lipper Multiple Myeloma Disease Center, Dana-Farber Cancer Institute, Harvard Medical School
    Boston Veterans Administration Healthcare System, West Roxbury, Massachusetts 02132, USA.)

  • Hiromi Nakamura

    (National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.)

  • Paul A. Northcott

    (German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.)

  • Marina Pajic

    (Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.)

  • Elli Papaemmanuil

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

  • Angelo Paradiso

    (Clinical Experimental Oncology Laboratory, National Cancer Institute, Via Amendola, 209, 70126 Bari, Italy.)

  • John V. Pearson

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.)

  • Xose S. Puente

    (IUOPA-Universidad de Oviedo, 33006 Oviedo, Spain.)

  • Keiran Raine

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

  • Manasa Ramakrishna

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

  • Andrea L. Richardson

    (Dana-Farber Cancer Institute, 450 Brookline Avenue
    Harvard Medical School
    Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA.)

  • Julia Richter

    (Institute of Human Genetics, Christian-Albrechts-University, 24118 Kiel, Germany.)

  • Philip Rosenstiel

    (Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24118 Kiel, Germany.)

  • Matthias Schlesner

    (German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.)

  • Ton N. Schumacher

    (The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.)

  • Paul N. Span

    (Radboud University Nijmegen Medical Centre, PO Box 9101, 6500HB Nijmegen, The Netherlands.)

  • Jon W. Teague

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

  • Yasushi Totoki

    (National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.)

  • Andrew N. J. Tutt

    (Breakthrough Breast Cancer Research Unit, King’s College London School of Medicine, London SW3 6JB, UK.)

  • Rafael Valdés-Mas

    (IUOPA-Universidad de Oviedo, 33006 Oviedo, Spain.)

  • Marit M. van Buuren

    (The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.)

  • Laura van ’t Veer

    (The Netherlands Cancer Institute, 121 Plesmanlaan, 1066 CX Amsterdam, The Netherlands.)

  • Anne Vincent-Salomon

    (Institut Curie, Departement de Pathologie, INSERM U830, 26 rue d’Ulm, 75248 Paris Cedex 05, France.)

  • Nicola Waddell

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.)

  • Lucy R. Yates

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

  • Jessica Zucman-Rossi

    (INSERM, UMR-674, Génomique Fonctionnelle des Tumeurs Solides, Institut Universitaire d’Hematologie (IUH), 75475 Paris, France.
    Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, 75006 Paris, France.)

  • P. Andrew Futreal

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

  • Ultan McDermott

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

  • Peter Lichter

    (German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.)

  • Matthew Meyerson

    (The Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute, 450 Brookline Avenue
    Harvard Medical School)

  • Sean M. Grimmond

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.)

  • Reiner Siebert

    (Institute of Human Genetics, Christian-Albrechts-University, 24118 Kiel, Germany.)

  • Elías Campo

    (Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Universitat de Barcelona, IDIBAPS, 08036 Barcelona, Spain.)

  • Tatsuhiro Shibata

    (National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.)

  • Stefan M. Pfister

    (German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
    69120 Heidelberg, Germany.)

  • Peter J. Campbell

    (Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
    Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK.
    University of Cambridge, Cambridge CB2 2XY, UK.)

  • Michael R. Stratton

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

Abstract

All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, ‘kataegis’, is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.

Suggested Citation

  • Ludmil B. Alexandrov & Serena Nik-Zainal & David C. Wedge & Samuel A. J. R. Aparicio & Sam Behjati & Andrew V. Biankin & Graham R. Bignell & Niccolò Bolli & Ake Borg & Anne-Lise Børresen-Dale & Sandri, 2013. "Signatures of mutational processes in human cancer," Nature, Nature, vol. 500(7463), pages 415-421, August.
    • Handle: RePEc:nat:nature:v:500:y:2013:i:7463:d:10.1038_nature12477
    DOI: 10.1038/nature12477
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