Abstract
Mutation signature analysis has been used to infer the contributions of various DNA mutagenic-repair events in individual cancer genomes. Here, we build a statistical framework using a multinomial distribution to assign individual mutations to their cognate mutation signatures. We applied it to 47 million somatic mutations in 1925 publicly available cancer genomes to obtain a mutation signature map at the resolution of individual somatic mutations. Based on mutation signature-level genetic-epigenetic correlative analyses, mutations with transcriptional and replicative strand asymmetries show different enrichment patterns across genomes, and "transcribed" chromatin states and gene boundaries are particularly vulnerable to transcription-coupled repair activities. While causative processes of cancer-driving mutations can be diverse, as shown for converging effects of multiple mutational processes on TP53 mutations, the substantial fraction of recurrently mutated amino acids points to specific mutational processes, e.g., age-related C-to-T transition for KRAS p.G12 mutations. Our investigation of evolutionary trajectories with respect to mutation signatures further revealed that candidate pairs of early- vs. late-operative mutation processes in cancer genomes represent evolutionary dynamics of multiple mutational processes in the shaping of cancer genomes. We also observed that the local mutation clusters of kataegis often include mutations arising from multiple mutational processes, suggestive of a locally synchronous impact of multiple mutational processes on cancer genomes. Taken together, our examination of the genome-wide landscape of mutation signatures at the resolution of individual somatic mutations shows the spatially and temporally distinct mutagenesis-repair-replication histories of various mutational processes and their effects on shaping cancer genomes.