The repertoire of mutational signatures in human cancer.

Autor: Alexandrov LB; Department of Cellular and Molecular Medicine, Department of Bioengineering, Moores Cancer Center, University of California, San Diego, CA, USA., Kim J; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Haradhvala NJ; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA., Huang MN; Programme in Cancer & Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.; Centre for Computational Biology, Duke-NUS Medical School, Singapore, Singapore., Tian Ng AW; Programme in Cancer & Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.; Centre for Computational Biology, Duke-NUS Medical School, Singapore, Singapore., Wu Y; Programme in Cancer & Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.; Centre for Computational Biology, Duke-NUS Medical School, Singapore, Singapore., Boot A; Programme in Cancer & Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.; Centre for Computational Biology, Duke-NUS Medical School, Singapore, Singapore., Covington KR; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA., Gordenin DA; Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences (NIEHS), Durham, NC, USA., Bergstrom EN; Department of Cellular and Molecular Medicine, Department of Bioengineering, Moores Cancer Center, University of California, San Diego, CA, USA., Islam SMA; Department of Cellular and Molecular Medicine, Department of Bioengineering, Moores Cancer Center, University of California, San Diego, CA, USA., Lopez-Bigas N; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.; Research Program on Biomedical Informatics, Universitat Pompeu Fabra, Barcelona, Spain.; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain., Klimczak LJ; Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences (NIEHS), Durham, NC, USA., McPherson JR; Programme in Cancer & Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.; Centre for Computational Biology, Duke-NUS Medical School, Singapore, Singapore., Morganella S; Wellcome Sanger Institute, Hinxton, UK., Sabarinathan R; Research Program on Biomedical Informatics, Universitat Pompeu Fabra, Barcelona, Spain.; National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India.; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain., Wheeler DA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Mustonen V; Department of Computer Science, University of Helsinki, Helsinki, Finland.; Organismal and Evolutionary Biology Research Programme, University of Helsinki, Helsinki, Finland.; Institute of Biotechnology, University of Helsinki, Helsinki, Finland., Getz G; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA., Rozen SG; Programme in Cancer & Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore. steverozen@gmail.com.; Centre for Computational Biology, Duke-NUS Medical School, Singapore, Singapore. steverozen@gmail.com.; SingHealth, Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore, Singapore, Singapore. steverozen@gmail.com., Stratton MR; Wellcome Sanger Institute, Hinxton, UK. mrs@sanger.ac.uk.
Jazyk: angličtina
Zdroj: Nature [Nature] 2020 Feb; Vol. 578 (7793), pp. 94-101. Date of Electronic Publication: 2020 Feb 05.
DOI: 10.1038/s41586-020-1943-3
Abstrakt: Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature 1 . Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium 2 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 analyses 3-15 , 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.
Databáze: MEDLINE
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