Somatic mutation load and spectra: A record of DNA damage and repair in healthy human cells

Abstract

Somatic genome instability is a hallmark of cancer genomes and has been linked to aging and a variety of other pathologies. Large-scale cancer genome and exome sequencing have revealed that mutation load and spectra in cancers can be influenced by environmental exposures, the anatomical site of exposures, and tissue type. There is now an abundance of data favoring the hypothesis that a substantial portion of the mutations in cancers originate prior to carcinogenesis in stem cells of the healthy individual. Rapid advances in sequencing of noncancer cells from healthy humans have shown that their mutation loads and spectra resemble cancer data. Similar to cancer genomes, mutation profiles of healthy cells show marked intra-individual variation, thus providing a metric of the various factors-environmental and endogenous-involved in mutagenesis in these individuals. This review focuses on the current methodologies to measure mutation loads and to determine mutation signatures for evaluating the environmental and endogenous sources of DNA damage in human somatic cells. We anticipate that in future, such large-scale studies aimed at exploring the landscapes of somatic mutations across different cell types in healthy people would provide a valuable resource for designing personalized preventative strategies against diseases associated with somatic genome instability. Environ. Mol. Mutagen. 59:672-686, 2018. Published 2018. This article is a U.S. Government work and is in the public domain in the USA.

Pan‐cancer genomic analyses reveal prognostic and immunogenic features of the tumor melatonergic microenvironment across 14 solid cancer types

“…Our findings indicated that patients with a low melatonin synthesis/metabolism Index tended to harbor a higher number of somatic mutations and/or neoantigens, and would be potentially more likely to benefit from immunotherapies. Somatic genome instability is a hallmark of cancer genomes, and a highly complex mutation landscape has been reported to originate from distinct DNA damage and repair processes . Previous research has also demonstrated that somatic mutations can subsequently generate neoantigens, which in turn could be recognized by the immune system, triggering an anticancer immune response and therefore likely to be associated with favorable responses to immunotherapy .…”

“…Somatic genome instability is a hallmark of cancer genomes, and a highly complex mutation landscape has been reported to originate from distinct DNA damage and repair processes. 38 Previous research has also demonstrated that somatic mutations can subsequently generate neoantigens, 13,14 which in turn could be recognized F I G U R E 6 Biological and clinical relevance of the tumor melatonergic microenvironment classification based on a two-gene mRNA expression model. The tumor melatonergic microenvironment is categorized into high vs low subgroups based on median values of melatonin synthesis/metabolism Index.…”

Enhanced C/EBPs binding to C>T mismatches facilitates fixation of CpG mutations

“…Different organs and tissues exhibit different probability to develop cancer, which can be explained by the number of divisions of the respective adult stem cell (ASC) (Tomasetti and Vogelstein, 2015). Thus, studying of mutational processes in stem cells is crucial to understand the tumorigenesis (Blokzijl et al, 2016;Franco et al, 2019;Rouhani et al, 2016;Saini and Gordenin, 2018;Yoshihara et al, 2017).…”

“…Nevertheless, alterations in regulatory regions are associated with many complex traits (Deplancke et al, 2016). Particularly, there are recurrent functional mutations in regulatory regions (Saini and Gordenin, 2018), such as the well-studied recurrent C>T transition that creates a strong binding site for the GABP transcription factor in the TERT promoter and is associated with increased cancer risk (Bell et al, 2015;Horn et al, 2013;Vinothkumar et al, 2020). Somatic mutations are caused by a combination of DNA damage and DNA repair failures (Volkova et al, 2020).…”

DNA damage and macrophage infiltration in the ovaries of the long-lived GH deficient Ames Dwarf and the short-lived bGH transgenic mice

“…Several factors can influence fertility during aging. The adverse effects of DNA damage caused by environmental factors on somatic cells have been extensively reported [18]. Mammalian oocytes enclosed in primordial follicles remain arrested in prophase I of meiosis up to several decades in some species, including humans [19, 20].…”