Abstract
Although a majority of somatic mutations in cancer are passengers, their mutational signatures provide mechanistic insights into mutagenesis and DNA repair processes. Mutational signature SBS8 is common in most cancers, but its etiology is debated. Incorporating genomic, epigenomic, and cellular process features for multiple cell-types we develop genome-wide composite epigenomic context-maps relevant for mutagenesis and DNA repair. Analyzing somatic mutation data from multiple cancer types in their epigenomic contexts, we show that SBS8 preferentially occurs in gene-poor, lamina-proximal, late replicating heterochromatin domains. While SBS8 is uncommon among mutations in non-malignant tissues, in tumor genomes its proportions increase with replication timing and speed, and checkpoint defects further promote this signature - suggesting that SBS8 probably arises due to uncorrected late replication errors during cancer progression. Our observations offer a potential reconciliation among different perspectives in the debate about the etiology of SBS8 and its relationship with other mutational signatures.
Highlights
A majority of somatic mutations in cancer are passengers, their mutational signatures provide mechanistic insights into mutagenesis and DNA repair processes
We develop an epigenomic composite context-map of the genome incorporating genomic, epigenomic, and cellular process features that are relevant for mutagenesis and DNA repair, and examine whether SBS8 preferentially occur in specific epigenomic context that could provide etiological insights
Since the mechanisms of endo- and exogenous DNA damage and repair preferences depend on local sequence, chromatin, and nuclear contexts[14], we segmented the genome based on (i) genomic contexts: exons, whole genes, repeats, and telomere, (ii) epigenomic contexts: strong heterochromatin, weak heterochromatin, intermediate chromatin, weak euchromatin, and strong euchromatin, and (iii) nuclear localization contexts: Fig. 1 Genomic and epigenomic context-preference for SBS8 in different cancer cohorts. a Relative frequencies of single base substitutions at 96 trinucleotide contexts for mutational signature SBS8. b Boxplots showing distributions of weights of SBS8 (w) in multiple cancer cohorts. c–k Boxplots showing distributions of weights of SBS8 (w) in different genomic, epigenomic, and nuclear localization contexts in multiple cancer types listed above
Summary
A majority of somatic mutations in cancer are passengers, their mutational signatures provide mechanistic insights into mutagenesis and DNA repair processes. Incorporating genomic, epigenomic, and cellular process features for multiple cell-types we develop genome-wide composite epigenomic context-maps relevant for mutagenesis and DNA repair. Even though a majority of the somatic mutations are not disease-drivers, mutational signatures, i.e., their patterns of genetic changes provide insights into past exposure to mutagens, mechanism of DNA damage, DNA repair defects, and extent of genomic instability[2,3,4,5,6,7]. We develop an epigenomic composite context-map of the genome incorporating genomic, epigenomic, and cellular process features that are relevant for mutagenesis and DNA repair, and examine whether SBS8 preferentially occur in specific epigenomic context that could provide etiological insights. Our context-guided analysis provides a rational roadmap for investigating etiologies of the emerging mutational signatures
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