Mutational Signatures and the Etiology of Human Cancers

Signatures of replication timing, recombination, and sex in the spectrum of rare variants on the human X chromosome and autosomes

“…The association of C > A and T > A mutations with replication timing does not necessarily imply that they are “replicative” in origin, i.e., due to errors directly introduced by the replication machinery while copying intact DNA, as they could also reflect greater unrepaired damage in later replicating regions (26). In particular, since C > A mutations are a known consequence of oxidative damage in somatic tissues (4, 5, 49–51), it is plausible that these mutations accumulate in regions of late replication due to greater damage to exposed single-stranded DNA, or poorer repair in these regions.…”

“…A possible explanation is that the X accrues excess C > A mutations because it replicates late in the germline. C > A mutations are known to be associated with oxidative damage (4, 5, 49–51), which remains unrepaired in sperm (17), and is likely repaired at or before the first cell division in the zygote (53–55). Late replication of the X chromosome at this stage, perhaps due to the inactive status of the paternally inherited X in female embryos (56), could then indeed be expected to result in an enrichment of C > A mutations on the X relative to autosomes, despite a primarily male source of damage.…”

“…The biochemical machinery that underlies germline mutagenesis can be conceptualized as a set of genetic loci that modulate the net mutational input in each generation, and variants in these loci as “modifiers of mutation” (2, 3). Since the activity of distinct biochemical pathways often leaves different signatures in DNA (4–10), these modifiers influence the distribution of mutation types (the “mutation spectrum”), as well as the total number of mutations inherited by offspring.…”

“…Such an approach has led to a wealth of insight into the sources of somatic mutations, i.e., mutations that accumulate in somatic tissues during normal development or aging. Distinct signatures of processes that generate or repair DNA lesions have been identified by analyzing millions of somatic mutations in their immediate sequence context, across tumor samples of diverse etiologies (4, 5, 7, 10). A complementary approach, based on changes in the mutation spectrum with regional variation in genomic features, has further illuminated the influence of local replication timing, transcription, chromatin organization, and epigenetic modifications on somatic mutagenesis (19–28).…”

DNA damage and somatic mutations in mammalian cells after irradiation with a nail polish dryer

“…Previously, we have shown that different endogenous and exogenous mutational processes imprint characteristic patterns of somatic mutations, termed, mutational signatures 33–35 . To evaluate the mutational signatures imprinted by irradiation with a UV-nail polish dryer, we first constructed background mutational models based on the continuously ongoing clock-like mutational signatures 36 and the mutational patterns observed in the spontaneous MEF and HFF clones, respectively.…”