Journal Article

The repertoire of mutational signatures in human cancer

Covington, Kyle R., Bergstrom, Erik N., Mustonen, Ville, Morganella, Sandro, Gordenin, Dmitry A., Alexandrov, Ludmil B., Rozen, Steven G., Wu, Yang, McPherson, John R., Kim, Jaegil, Klimczak, Leszek J., Huang, Mi Ni, Lopez-Bigas, Nuria, Boot, Arnoud, Wheeler, David A., Haradhvala, Nicholas J., Tian Ng, Alvin Wei, Sabarinathan, Radhakrishnan, Getz, Gad, Islam, S. M. Ashiqul, Stratton, Michael R.

2020

Overview

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. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 45/23 / 631/208/737 / 631/67/68 / Age Factors / Base Sequence / Basic Medicine / Cancer / Consortia / Deoxyribonucleic acid / DNA / DNA damage / DNA repair / Exome - genetics / Gene deletion / Gene mutations / Gene sequencing / Genetic aspects / Genome, Human - genetics / Genomes / Health aspects / Humanities and Social Sciences / Humans / Identification and classification / Insertion / Medical and Health Sciences / Medical Genetics and Genomics (including Gene Therapy) / Medicin och hälsovetenskap / Medicinsk genetik och genomik (Här ingår: Genterapi) / Medicinska och farmaceutiska grundvetenskaper / multidisciplinary / Mutation / Mutation - genetics / Neoplasms - genetics / Science / Science (multidisciplinary) / Sequence Analysis, DNA / Signatures / Substitutes / Tumors