The repertoire of mutational signatures in human cancer

By Ludmil B. Alexandrov, Jaegil Kim, N. Haradhvala, Mi Huang, A. Ng, Yingting Wu, Arnoud Boot, K. Covington, D. Gordenin, E. Bergstrom and 11 more. Nature, 2018

3,063 citations recorded by the source corpus.

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. The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

Subfields: Cancer Research, Genetics

View Paper: https://www.semanticscholar.org/paper/3296bd0d691117f8d69afa0ae684a1bb30c33013

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Citations in the corpus

COSMIC: a curated database of somatic variants and clinical data for cancer (2023, positive): “….sanger . ac.uk/ signatures/ ) is a resource developed as part of the CRUK Mutographs Cancer Grand Challenge and a collaborative project involving the Wellcome Sanger Institute, the Pillay lab at University College London, and the Alexandrov lab at the University of California ( 17 ).”
Genomic basis for RNA alterations in cancer (2020, methodology): “9), which has previously been reported in cancer 17 .”
Uncovering novel mutational signatures by de novo extraction with SigProfilerExtractor (2020, positive): “1 reference signatures.(12) The decomposition functionality leverages the nonnegative least squares (NNLS) algorithm(326) as its main computational engine.”
The landscape of somatic mutation in normal colorectal epithelial cells (2018, background): “Colorectal adenocarcinoma signature attributions and burden are 529 from Alexandrov et al.(1).”
Patterns of somatic structural variation in human cancer genomes (2020, neutral): “Liver−HCC (312) Lymph−BNHL (107) Kidney−ChRCC (43) Panc−Endocrine (81) Biliary−AdenoCA (33) SoftTissue−Leiomyo (15) Lung−AdenoCA (37) Skin−Melanoma (106) Uterus−AdenoCA (42) Panc−AdenoCA (230) Breast−AdenoCA (192) Cervix−SCC (18) Lung−SCC (47) Head−SCC (56) Bone−Osteosarc (34) Ovary−AdenoCA (109) Es”
Immune Cell Abundance and T-cell Receptor Landscapes Suggest New Patient Stratification Strategies in Head and Neck Squamous Cell Carcinoma (2023, background): “Re-centefforts(33,34)havedelineatedevidencefromvariousmutationalprocesses contributing to cancer development in the form of genome-wide trinucleotide substitution patterns, which associate with various types of DNA damage and are indicative of environmental and intrinsic neoplastic risk factors…”