Mechanisms of Base Substitution Mutagenesis in Cancer Genomes

Abstract

Cancer genome sequence data provide an invaluable resource for inferring the key mechanisms by which mutations arise in cancer cells, favoring their survival, proliferation and invasiveness. Here we examine recent advances in understanding the molecular mechanisms responsible for the predominant type of genetic alteration found in cancer cells, somatic single base substitutions (SBSs). Cytosine methylation, demethylation and deamination, charge transfer reactions in DNA, DNA replication timing, chromatin status and altered DNA proofreading activities are all now known to contribute to the mechanisms leading to base substitution mutagenesis. We review current hypotheses as to the major processes that give rise to SBSs and evaluate their relative relevance in the light of knowledge acquired from cancer genome sequencing projects and the study of base modifications, DNA repair and lesion bypass. Although gene expression data on APOBEC3B enzymes provide support for a role in cancer mutagenesis through U:G mismatch intermediates, the enzyme preference for single-stranded DNA may limit its activity genome-wide. For SBSs at both CG:CG and YC:GR sites, we outline evidence for a prominent role of damage by charge transfer reactions that follow interactions of the DNA with reactive oxygen species (ROS) and other endogenous or exogenous electron-abstracting molecules.

Hypermutation in human cancer genomes: footprints and mechanisms

“…Highly mutagenic 8-oxo-7,8 dihydroguanine (8-oxoG) could be the reason for such a bias, however other products of reactions of guanine and cytosine could also contribute 94 . Vasquez and colleagues 99, 100 found the mutation motif [(A|T|G|C)(T|C) C (A|T|C)]) is enriched in several cancers. Experimentally, they found that guanines in the complementary sequence context have a higher potential to trap electrons and thus have an increased chance of chemical modification.…”

“…Examples listed in TAB. 2 and below (see also 99, 147 ) can be used to illustrate these lines of analysis.…”

Clusters of Multiple Mutations: Incidence and Molecular Mechanisms

“…Several prominent mutation signatures consisting of mutated nucleotide and immediate (1–2 nucleotides) surrounding context (reviewed in (5; 10; 53; 94; 106)) have been identified. Another striking pattern of mutagenesis revealed by genome-wide sequencing of multiple samples of several cancer types was the presence of many mutation clusters (up to several hundred per sample, see Table 1; also reviewed in (104; 105)), identified by two independent and complementary analytical methods.…”

Mutation tendency of mutator Plasmodium berghei with proofreading-deficient DNA polymerase δ

“…S1). However, our sample size was small and a more detailed analysis with more replicates will be necessary to conclusively elucidate the mutation spectrum at T C T. Interestingly, a markedly elevated mutation rate at T C T has also been reported in cancer genomes with proofreading-deficient Pol ε264142. The proofreading-deficient human Pol ε exhibits a preference for T C T to T A T transversions in vitro 26, and thus the deamination of me 5 C does not appear to be involved in the elevated mutation rate in tumours.…”