The repertoire of mutational signatures in human cancer

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  • dc.contributor.author Alexandrov, Ludmil B.
  • dc.contributor.author López Bigas, Núria
  • dc.contributor.author PCAWG Consortium
  • dc.date.accessioned 2021-01-29T11:24:10Z
  • dc.date.available 2021-01-29T11:24:10Z
  • dc.date.issued 2020
  • dc.description.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.
  • dc.description.sponsorship This work was supported by Wellcome grant reference 206194 (M.R.S.), Singapore National Medical Research Council grants NMRC/CIRG/1422/2015 and MOH-000032/MOH-CIRG18may-0004 and the Singapore Ministry of Health via the Duke-NUS Signature Research Programmes (M.N.H., A.W.T.N., Y.W., A.B. and S.G.R.), US National Institute of Health Intramural Research Program Project Z1AES103266 (D.A.G.), the European Research Council Consolidator Grant 682398 (N.L.-B.), US National Cancer Institute U24CA143843 (D.A.W.) and Cancer Research UK Grand Challenge Award C98/A24032 (E.N.B., S.M.A.I., L.B.A. and M.R.S.). G.G and J.K were partially supported by the National Cancer Institute grants U24CA210999 and U24CA143845. G.G. was partially supported by the Paul C. Zamecnick, MD, Chair in Oncology at the Massachusetts General Hospital Cancer Center. N.J.H. and G.G. were partially supported by G.G.’s funds at the Broad Institute and Massachusetts General Hospital. N.J.H. was partially funded by the Molecular Biophysics Training Grant NIH/ NIGMS T32 GM008313 (PI: Venkatesh N. Murthy).We acknowledge the contributions of the many clinical networks across the ICGC and TCGA who provided samples and data to the PCAWG Consortium, and the contributions of the Technical Working Group and the Germline Working Group of the PCAWG Consortium for collation, realignment and harmonized variant calling of the cancer genomes used in this study.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Alexandrov LB, Kim J, Haradhvala NJ, Huang MN, Tian Ng AW, Wu Y et al. The repertoire of mutational signatures in human cancer. Nature. 2020; 578(7793):94-101. DOI: 10.1038/s41586-020-1943-3
  • dc.identifier.doi http://dx.doi.org/10.1038/s41586-020-1943-3
  • dc.identifier.issn 0028-0836
  • dc.identifier.uri http://hdl.handle.net/10230/46296
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Nature. 2020; 578(7793):94-101
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/682398
  • dc.rights © The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Cancer genetics
  • dc.subject.keyword Mutation
  • dc.title The repertoire of mutational signatures in human cancer
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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