The repertoire of mutational signatures in human cancer

Abstract

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. Somatic mutations in cancer genomes are caused by mutational processes of both exogenous and endogenous origin that operate during the cell lineage between the fertilized egg and the cancer cell 16. Each mutational process may involve components of DNA damage or modification, DNA repair and DNA replication (which may be normal or abnormal), and generates a characteristic mutational signature that potentially includes base substitutions, small insertions and deletions (indels), genome rearrangements and chromosome copy-number changes 1. The mutations in an individual cancer genome may have been generated by multiple mutational processes, and thus incorporate multiple superimposed mutational signatures. Therefore, to systematically characterize the mutational processes that contribute to cancer, mathematical methods have previously been used to decipher mutational signatures from somatic mutation catalogues, estimate the number of mutations that are attributable to each signature in individual samples and annotate each mutation class in each tumour with the probability that it arose from each signature 6,9,17-27. Previous studies of multiple types of cancer have identified more than 30 single-base substitution (SBS) signatures, some of knownbut many of unknown-aetiologies, some ubiquitous and others rare, some part of normal cell biology and others associated with abnormal exposures or neoplastic progression 3-5,7-15. Genome rearrangement signatures have also previously been described 11,25,28-30. However, the analysis of other classes of mutation has been relatively limited 3,11,31-33 .

Global genomics project unravels cancer’s complexity at unprecedented scale

“…In the third and fourth papers, Alexandrov et al 3 Notably, Li and colleagues are among the first to uncover reproducible signatures involving structural variants (SVs) -re arrangements of large portions of the genome. The process was much more intricate than that for identifying mutational signatures because of the diversity and complexity of SVs.…”

“…Since then, advances in sequencing technology and analytical tools have allowed this research field to flourish. In six papers [1][2][3][4][5][6] in this issue of Nature, the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium presents the most comprehensive and ambitious meta-analysis of cancer genomes so far. Unlike previous efforts that focused largely on protein-coding regions of the cancer genome, PCAWG analyses whole genomes.…”

Enhanced C/EBPs binding to C>T mismatches facilitates fixation of CpG mutations

“…Signature 1 (called SBS1 in (Alexandrov et al, 2020) and Sig.B in (Blokzijl et al, 2016)) represents mainly the C to T transitions in CpG contexts resulting from spontaneous deamination of methylated cytosine into thymine (Alexandrov et al, 2013;Blokzijl et al, 2016). This mutational process plays a major role in small intestinal and colon ASCs ( Fig EV1B).…”

“…Somatic mutations are caused by a combination of DNA damage and DNA repair failures (Volkova et al, 2020). The interplay of these processes can produce mutation sets in different preferred genomic contexts, the so-called mutation signatures (Alexandrov et al, 2020(Alexandrov et al, , 2013, with varying impact on creation or disruption of transcription factor binding motifs (Yiu Chan et al, 2019). In cancer, the overall patterns of mutational processes in transcription factor binding sites are very complex, due to the interference of numerous incidental circumstances, both local, such as the extended context of mutation signatures (Fredriksson et al, 2017), and global, such as the pressure of clonal selection (Vorontsov et al, 2016).…”

A versatile system to introduce clusters of genomic double-strand breaks in large cell populations

“…Single nucleotide variants (SNV) were called by Mutect2 10 . Resulting somatic SNVs were converted to 96-classes of trinucleotide context profiles by the PCAWG signature preparation tool 11 . Trinucleotide context profiles were used as input for sigProfiler 11 to perform a mutational signature analysis and to retrieve the signature exposures of 45 SNV signatures from COSMIC single base substitution (SBS) signatures V3.…”