Regional mutational signature activities in cancer genomes

Cancer genomes harbor a catalog of somatic mutations. The type and genomic context of these mutations depend on their causes and allow their attribution to particular mutational signatures. Previous work has shown that mutational signature activities change over the course of tumor development, but investigations of genomic region variability in mutational signatures have been limited. Here, we expand upon this work by constructing regional profiles of mutational signature activities over 2,203 whole genomes across 25 tumor types, using data aggregated by the Pan-Cancer Analysis of Whole Genomes (PCAWG) consortium. We present GenomeTrackSig as an extension to the TrackSig R package to construct regional signature profiles using optimal segmentation and the expectation-maximization (EM) algorithm. We find that 426 genomes from 20 tumor types display at least one change in mutational signature activities (changepoint), and 306 genomes contain at least one of 54 recurrent changepoints shared by seven or more genomes of the same tumor type. Five recurrent changepoint locations are shared by multiple tumor types. Within these regions, the particular signature changes are often consistent across samples of the same type and some, but not all, are characterized by signatures associated with subclonal expansion. The changepoints we found cannot strictly be explained by gene density, mutation density, or cell-of-origin chromatin state. We hypothesize that they reflect a confluence of factors including evolutionary timing of mutational processes, regional differences in somatic mutation rate, large-scale changes in chromatin state that may be tissue type-specific, and changes in chromatin accessibility during subclonal expansion. These results provide insight into the regional effects of DNA damage and repair processes, and may help us localize genomic and epigenomic changes that occur during cancer development. Author summary Somatic mutations accumulate through cancer development. These mutations are the result of DNA damage and DNA repair deficiencies; in some cases these mutation sources can be recovered by attributing mutations to different mutational signatures. Mutational signatures describe patterns of co-occurring substitution types (e.g., C to A) that are associated with various mutagenic processes. For example, UV radiation causes CpC to TpT substitutions, and smoking mutagens are associated with C to A substitution. Previous work has shown that mutational signature activities in cancer genomes change over the course of a cancer's development. Less is known about how their activities change across the entire genome, which is relevant for understanding the regional effects of DNA damage and repair deficiencies. We have developed a bioinformatic tool GenomeTrackSig, which uses a segmentation algorithm to estimate mutational signature activities across large chromosomal domains and identify changepoints where activities vary. We apply GenomeTrackSig to 2,203 cancer genomes and find that 426 contain changepoints. Some changepoints recur across multiple samples of the same type, and some also exhibit activity tradeoffs between signatures active in either early or late cancer development. Changepoints cannot be explained well by genomic factors that typically contribute to mutation rate variation. We hypothesize that they are driven by a confluence of factors, including large-scale changes in chromatin state that may occur over cancer evolution.

Automated summary

This study presents regional profiles of mutational signature activities in cancer genomes, showcasing changes in these activities during tumor development. The research reveals shared changepoints across multiple tumor types and activity tradeoffs between signatures active in early and late cancer development.