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The repertoire of mutational signatures in human cancer

Alexandrov, Ludmil B ; Kim, Jaegil ; Haradhvala, Nicholas J ; Huang, Mi Ni LU ; Tian Ng, Alvin Wei ; Wu, Yang ; Boot, Arnoud ; Covington, Kyle R ; Gordenin, Dmitry A and Bergstrom, Erik N , et al. (2020) In Nature 578(7793). p.94-101
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... (More)

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.

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LU ; LU orcid and LU orcid
author collaboration
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Contribution to journal
publication status
published
subject
keywords
Age Factors, Base Sequence, Exome/genetics, Genome, Human/genetics, Humans, Mutation/genetics, Neoplasms/genetics, Sequence Analysis, DNA
in
Nature
volume
578
issue
7793
pages
94 - 101
publisher
Nature Publishing Group
external identifiers
  • pmid:32025018
  • scopus:85079072353
ISSN
0028-0836
DOI
10.1038/s41586-020-1943-3
language
English
LU publication?
yes
id
fb1d7b95-8891-424b-bdc0-fc6a9af5c286
date added to LUP
2023-03-29 17:18:29
date last changed
2025-03-23 09:11:05
@article{fb1d7b95-8891-424b-bdc0-fc6a9af5c286,
  abstract     = {{<p>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.</p>}},
  author       = {{Alexandrov, Ludmil B and Kim, Jaegil and Haradhvala, Nicholas J and Huang, Mi Ni and Tian Ng, Alvin Wei and Wu, Yang and Boot, Arnoud and Covington, Kyle R and Gordenin, Dmitry A and Bergstrom, Erik N and Islam, S M Ashiqul and Lopez-Bigas, Nuria and Klimczak, Leszek J and McPherson, John R and Morganella, Sandro and Sabarinathan, Radhakrishnan and Wheeler, David A and Mustonen, Ville and Getz, Gad and Rozen, Steven G and Stratton, Michael R}},
  issn         = {{0028-0836}},
  keywords     = {{Age Factors; Base Sequence; Exome/genetics; Genome, Human/genetics; Humans; Mutation/genetics; Neoplasms/genetics; Sequence Analysis, DNA}},
  language     = {{eng}},
  number       = {{7793}},
  pages        = {{94--101}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature}},
  title        = {{The repertoire of mutational signatures in human cancer}},
  url          = {{http://dx.doi.org/10.1038/s41586-020-1943-3}},
  doi          = {{10.1038/s41586-020-1943-3}},
  volume       = {{578}},
  year         = {{2020}},
}