Clock-like mutational processes in human somatic cells

Abstract

During the course of a lifetime somatic cells acquire mutations. Different mutational processes may contribute to the mutations accumulated in a cell, with each imprinting a mutational signature on the cell's genome. Some processes generate mutations throughout life at a constant rate in all individuals and the number of mutations in a cell attributable to these processes will be proportional to the chronological age of the person. Using mutations from 10,250 cancer genomes across 36 cancer types, we investigated clock-like mutational processes that have been operating in normal human cells. Two mutational signatures show clock-like properties. Both exhibit different mutation rates in different tissues. However, their mutation rates are not correlated indicating that the underlying processes are subject to different biological influences. For one signature, the rate of cell division may influence its mutation rate. This study provides the first survey of clock-like mutational processes operative in human somatic cells.

Ultra-deep sequencing detects ovarian cancer cells in peritoneal fluid and reveals somatic TP53 mutations in noncancerous tissues

“…Furthermore, 38.6% of C:G→T:A mutations occurred at CpG sites, which are known to be highly mutable and prone to deamination. These data are consistent with known mutational signatures in cancer associated with age, specifically signatures 1A and 1B reported in Alexandrov et al (25,26).…”

“…The age effect was observed for mutations detected in both exons and introns, and independently in the analysis of peritoneal fluid and peripheral blood. This age dependency is in concordance with prior studies of somatic mutations in noncancerous tissues (28-30, 32, 33) and supports the notion that "clock-like mutations" commonly found in cancers accumulate in normal cells with aging before the development of cancer (25). Third, a proportion (13/58) of the low frequency mutations found in blood were also detected in peritoneal fluid from the same patient.…”

The landscape of genomic alterations across childhood cancers

“…Most cancer types predominantly harboured C > T transitions (≥ 30% of SNVs in two-thirds of cancer types) linked to mutational signature 1, whose previously described age-association occurred in some paediatric brain tumours 15,16 (P < 0.05; Extended Data Figs 1g,. Mutational signatures, possibly reflecting biochemical cellular processes, have previously been investigated for many, mainly adult, cancers 15 .…”

Chemically-Induced DNA Damage, Mutagenesis, and Cancer

“…Resveratrol triggered apoptosis within human T-cell acute lymphoblastic leukemia MOLT-4 cells by abrogating Akt phosphorylation, and subsequently preventing GSK3β from being activated [135]. Similarly, resveratrol induced apoptosis in ovarian, [136] breast, [137] uterine, [138] prostate, [120] and multiple myeloma cells [121], via inhibiting Akt phosphorylation. Chen et al [139] determined that resveratrol inhibited the phosphorylation of PI3K/Akt (i.e., PI3K/Akt inactivation) in prostate cancer cells, resulting in decreased Forkhead box protein (FOXO) activation.…”

“…The advent of next-generation sequencing technologies has enabled large-scale sequencing of all protein-coding exons (whole-exome sequencing) or even whole cancer genomes (whole-genome sequencing) in a single experiment [132][133][134][135][136][137][138]. These sequencing efforts have enabled the identification of many thousands of mutations per cancer which provided sufficient power to detect different mutational patterns or "signatures."…”