SummaryMultiple signatures of somatic mutations have been identified in cancer genomes. Exome sequences of 1,001 human cancer cell lines and 577 xenografts revealed most common mutational signatures, indicating past activity of the underlying processes, usually in appropriate cancer types. To investigate ongoing patterns of mutational-signature generation, cell lines were cultured for extended periods and subsequently DNA sequenced. Signatures of discontinued exposures, including tobacco smoke and ultraviolet light, were not generated in vitro. Signatures of normal and defective DNA repair and replication continued to be generated at roughly stable mutation rates. Signatures of APOBEC cytidine deaminase DNA-editing exhibited substantial fluctuations in mutation rate over time with episodic bursts of mutations. The initiating factors for the bursts are unclear, although retrotransposon mobilization may contribute. The examined cell lines constitute a resource of live experimental models of mutational processes, which potentially retain patterns of activity and regulation operative in primary human cancers.

Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases1, while rare variants in CDK4, BRCA2, BAP1, and the promoter of TERT, have also been linked to the disease2-5. Here we set out to identify novel high-penetrance susceptibility genes in unexplained cases by sequencing 184 melanoma patients from 105 pedigrees recruited in the United Kingdom, the Netherlands, and Australia that were negative for variants in known predisposition genes. We identify families where melanoma co-segregates with loss-of-function variants in the protection of telomeres 1 (POT1) gene, a proportion of members presenting with an early age of onset and multiple primaries. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide-/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding, leading to increased telomere length. Thus, POT1 variants predispose to melanoma formation via a direct effect on telomeres.

IntroductionThe somatic mutations in a cancer genome are the aggregate outcome of one or more mutational processes operative through the life of the cancer patient1-3. Each mutational process leaves a characteristic mutational signature determined by the mechanisms of DNA damage and repair that constitute it. A role was recently proposed for the APOBEC family of cytidine deaminases in generating particular genome-wide mutational signatures1,4 and a signature of localized hypermutation called kataegis1,4. A germline copy number polymorphism involving APOBEC3A and APOBEC3B, which effectively deletes APOBEC3B5, has been associated with a modest increased risk of breast cancer6-8. Here, we show that breast cancers in carriers of the deletion show more mutations of the putative APOBEC-dependent genome-wide signatures than cancers in non-carriers. The results suggest that the APOBEC3A/3B germline deletion allele confers cancer susceptibility through increased activity of APOBEC-dependent mutational processes, although the mechanism by which this occurs remains unknown.

The somatic mutations present in the genome of a cell have been accumulated over the lifetime of a multicellular organism. These mutations can provide insights into the developmental lineage tree 1 , the number of divisions each cell has undergone and the mutational processes that have been operative 2 . Here, we conducted whole genome sequencing of clonal lines 3 derived from multiple tissues of healthy mice. Using somatic base substitutions, we reconstructed the early cell divisions of each animal demonstrating the contributions of embryonic cells to adult tissues. Differences were observed between tissues in the numbers and types of mutations accumulated by each cell, which likely reflect differences in the number of cell divisions they have undergone and varying contributions of different mutational processes. If somatic mutation rates are similar to those in mice, the results indicate that precise insights into development and mutagenesis of normal human cells will be possible.

Somatic cells acquire mutations throughout the course of an individual’s life. Mutations occurring early in embryogenesis will often be present in a substantial proportion of, but not all, cells in the post-natal human and thus have particular characteristics and impact1. Depending upon their location in the genome and the proportion of cells they are present in, these mosaic mutations can cause a wide range of genetic disease syndromes2 and predispose to cancer3,4. They have a high chance of being transmitted to offspring as de novo germline mutations and, in principle, can provide insights into early human embryonic cell lineages and their contributions to adult tissues5. Although it is known that gross chromosomal abnormalities are remarkably common in early human embryos6 our understanding of early embryonic somatic mutations is very limited. Here, we use whole genome sequences of adult normal blood from 241 individuals to identify 163 early embryonic mutations. We estimate that approximately three base substitution mutations occur per cell per cell-doubling in early human embryogenesis and these are mainly attributable to two known mutational signatures7. We used the mutations to reconstruct developmental lineages of adult cells and demonstrate that the two daughter cells of many early embryonic cell doublings contribute asymmetrically to adult blood at an approximately 2:1 ratio. This study therefore provides insights into the mutation rates, the mutational processes and the developmental outcomes of cell dynamics operative during early human embryogenesis.