Analysis of mutational signatures in C. elegans: Implications for cancer genome analysis

Genome integrity is constantly challenged by exogenous and endogenous insults, and mutations are associated with inherited disease and cancer. Here we summarize recent studies that utilized C. elegans whole genome next generation sequencing to experimentally determine mutational signatures associated with mutagen exposure, DNA repair deficiency or a combination of both and discuss the implications of these results for the understanding of cancer genome evolution. The experimental analysis of wild-type and DNA repair deficient nematodes propagated under unchallenged conditions over many generations revealed increased mutagenesis in approximately half of all DNA repair deficient strains, its rate, except for DNA mismatch repair, only being moderately increased. The exposure of wild-type and DNA repair defective strains to selected genotoxins, including UV-B and ionizing radiation, alkylating compounds, aristolochic acid, aflatoxin-B1, and cisplatin enabled the systematic analysis of the relative contributions of redundant repair modalities that mend DNA damage. Combining genotoxin exposure with DNA repair deficiency can manifest as altered mutation rates and/or as a change in mutational profiles, and reveals how different DNA alterations induced by one genotoxin are repaired by separate DNA repair pathways, often in a highly redundant way. Cancer genomes provide a snapshot of all mutational events that happened prior to cancer detection and sequencing, necessitating computational models to deduce mutational signatures using mathematical best fit approaches. While computationally deducing signatures from cancer genomes has been tremendously successful in associating some signatures to known mutagenic causes, many inferred signatures lack a clear link to a known mutagenic process. Moreover, analytical signatures might not reflect any distinct mutagenic processes. Nonetheless, combined effects of mutagen exposure and DNA damage-repair deficiency are also present in cancer genomes, but cannot be as easily detected owing to the unknown histories of genotoxic exposures and because biallelic in contrast to monoallelic DNA repair deficiency is rare. The impact of damage-repair interactions also manifests through selective pressure for DNA repair gene inactivation during cancer evolution. Using these considerations, we discuss a theoretical framework that explains why minute mutagenic changes, possibly too small to manifest as change in a signature, can have major effects in oncogenesis. Overall, the experimental analysis of mutational processes underscores that the interpretation of mutational signatures requires considering both the primary DNA lesion and repair status and imply that mutational signatures derived from cancer genomes may be more variable than currently anticipated.