The underlying causes of DNA mutations (alterations in one or more bases in the genome sequence) are known to include free radicals, irradiation, reactive oxygenated molecules, and “random events” (in part ionizing radiation to which every life form on the planet is exposed). DNA repair processes restore probably more than 99% of such mutations, but the fact that mutations and chromosomal rearrangements occur — is a necessary and important part of evolution. If such “fixed” alterations occur early enough in embryonic development, the changes are inherited by all of an organism’s cells. However, if these alterations arise later in adult life, it is more difficult to track such changes in a small number of cells in a specific tissue; thus, the extent of these alterations in normal tissues is poorly understood.
It is believed that cancer is initiated when cells acquire a minimum compendium of genetic alterations needed to trigger tumor formation. Understanding when such initiating mutations occur in normal cells — is crucial for enabling reconstruction of early events that lead to cancer. Authors [see attached article & editorial] analyzed the extent of mutations in human epithelial tissue (i.e. the lining) from the healthy esophagus, and how this relates to processes that drive cancer development.
Authors sequenced 74 cancer-associated genes in 844 tissue samples, taken from the upper esophagus of nine healthy donors. For 21 of these 844 samples, authors also carried out whole-genome sequencing (WGS). A previous study assessing mutations in healthy skin cells — had found between two and six mutations per million DNA nucleotides. In contrast, the attached article describes that mutations in esophageal cells arose at a roughly 10-fold lower rate than that reported for skin. This difference is probably not surprising, because skin cells are exposed to more DNA-damaging agents (e.g. ultraviolet light) than are esophageal cells.
Interestingly, however, compared with healthy skin — the healthy esophagus has more mutations in cancer-associated genes. Moreover, at least a subset of these altered genes was under strong positive selection (meaning that these genetic alterations promoted cell proliferation, leading to formation of cell clones). Authors found that driver-mutated clones emerge multifocally — from early childhood (and increase in number and size with aging, ultimately replacing almost the entire esophageal epithelium in the extremely elderly). Compared with mutations in esophageal cancer, there is marked over-representation of NOTCH1 and PPM1D (known cancer-associated genes) mutations in physiologically normal esophageal epithelia; these mutations often appear before late adolescence (but as early as early infancy!!) and significantly increase in number with heavy smoking and drinking.
Authors conclude that remodeling of the esophageal epithelium by driver-mutated clones is an inevitable consequence of normal aging, which — depending on lifestyle risks — may affect cancer development. But one remarkable finding of this study is how many “undesirable” mutations are sitting there, in almost everyone, without cancer developing. 🙂
Nature 17 Jan 2019; 565: 312–317 [Article] & pp 101–103 [News-N-Views]
this is a good point worth mentioning. I should have noted that.
This research project represents a massive amount of work.
But, the bottom line of this study is that the researchers used an N of 9 –– which is a very small number.