期刊
NATURE
卷 578, 期 7793, 页码 94-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41586-020-1943-3
关键词
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资金
- Wellcome grant [206194]
- Singapore National Medical Research Council [NMRC/CIRG/1422/2015, MOH-000032/MOHCIRG18may-0004]
- Singapore Ministry of Health via the Duke-NUS Signature Research Programmes
- US National Institute of Health Intramural Research Program Project [Z1AES103266]
- European Research Council [682398]
- US National Cancer Institute [U24CA143843]
- Cancer Research UK Grand Challenge Award [C98/A24032]
- National Cancer Institute [U24CA210999, U24CA143845]
- Paul C. Zamecnick, MD, Chair in Oncology at the Massachusetts General Hospital Cancer Center
- G.G.'s funds at the Broad Institute and Massachusetts General Hospital
- Molecular Biophysics Training Grant [NIH/NIGMS T32 GM008313]
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [ZIAES103266] Funding Source: NIH RePORTER
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.
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