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The repertoire of mutational signatures in human cancer

Author

Listed:
  • Ludmil B. Alexandrov

    (University of California)

  • Jaegil Kim

    (Broad Institute of MIT and Harvard)

  • Nicholas J. Haradhvala

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Mi Ni Huang

    (Duke-NUS Medical School
    Duke-NUS Medical School)

  • Alvin Wei Tian Ng

    (Duke-NUS Medical School
    Duke-NUS Medical School)

  • Yang Wu

    (Duke-NUS Medical School
    Duke-NUS Medical School)

  • Arnoud Boot

    (Duke-NUS Medical School
    Duke-NUS Medical School)

  • Kyle R. Covington

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Dmitry A. Gordenin

    (National Institute of Environmental Health Sciences (NIEHS))

  • Erik N. Bergstrom

    (University of California)

  • S. M. Ashiqul Islam

    (University of California)

  • Nuria Lopez-Bigas

    (The Barcelona Institute of Science and Technology
    Universitat Pompeu Fabra
    Institució Catalana de Recerca i Estudis Avançats (ICREA))

  • Leszek J. Klimczak

    (National Institute of Environmental Health Sciences (NIEHS))

  • John R. McPherson

    (Duke-NUS Medical School
    Duke-NUS Medical School)

  • Sandro Morganella

    (Wellcome Sanger Institute)

  • Radhakrishnan Sabarinathan

    (Universitat Pompeu Fabra
    National Centre for Biological Sciences, Tata Institute of Fundamental Research
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology)

  • David A. Wheeler

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Ville Mustonen

    (University of Helsinki
    University of Helsinki
    University of Helsinki)

  • Gad Getz

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Massachusetts General Hospital
    Harvard Medical School)

  • Steven G. Rozen

    (Duke-NUS Medical School
    Duke-NUS Medical School
    National Heart Centre Singapore)

  • Michael R. Stratton

    (Wellcome Sanger Institute)

Abstract

Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature1. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium2 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses3–15, enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated—but distinct—DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer.

Suggested Citation

  • Ludmil B. Alexandrov & Jaegil Kim & Nicholas J. Haradhvala & Mi Ni Huang & Alvin Wei Tian Ng & Yang Wu & Arnoud Boot & Kyle R. Covington & Dmitry A. Gordenin & Erik N. Bergstrom & S. M. Ashiqul Islam , 2020. "The repertoire of mutational signatures in human cancer," Nature, Nature, vol. 578(7793), pages 94-101, February.
  • Handle: RePEc:nat:nature:v:578:y:2020:i:7793:d:10.1038_s41586-020-1943-3
    DOI: 10.1038/s41586-020-1943-3
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