“Driver mutations” in human esophagus (as function of age), but appear not to lead to cancer Nebert, Daniel (nebertdw)

One manifestation of gene-environment interactions is that: environmental adversity can cause (presumably random) DNA mutations in various genes, as well as throughout the entire genome (keeping in mind that ~99% of the genome is DNA that does not code for proteins). “Environmental adversity” includes anything that can be mutagenic (i.e. able to cause a mutation); this could be chemicals in cigarette smoke or occupational exposure, endogenous compounds such as one’s own metabolites, or dietary substances such as metabolites of beefsteak or broccholi. It is well known that somatic cell mutations (as opposed to germ line mutations in ova or sperm) occur in healthy cells throughout our lives. Most of these mutations do not alter cell behavior and simply appear to accumulate passively. Occasionally, however, a key gene is altered in a way that provides a mutant cell with a competitive advantage, leading to the formation of persistent mutant clones of this aberrant cell.

Such clones are thought to be the origin of cancer initiation and have also been linked to other diseases. Despite the importance of somatic mutation, understanding its extent in normal tissues has been challenging, because of the difficulties of identifying mutations present in small numbers of cells. The most highly mutated normal tissue known is sunshine-exposed human skin. Deep-targeted sequencing of sun-exposed skin from middle-aged individuals revealed large numbers of mutant clones under positive selection, with about 25% of skin cells carrying cancer-driving mutations. Because most mutations are caused by ultraviolet (UV) light, it is unclear whether aged sun-exposed skin represents a special case — due to a lifetime of exposure to a powerful mutagen. This question motivated the authors [see attached article & editorial] to investigate the mutational landscape of esophageal epithelium (cells lining the esophagus), a tissue with a similar structure, but exposure to very different mutagens (i.e. dietary substances, instead of sunshine).

Like the skin, esophageal epithelium consists of layers of keratinocytes. Cells are shed from the surface throughout life and are replaced by proliferation of cells near the basement membrane. In addition, both skin — as well as upper and mid-esophagus — can develop squamous cell cancer. Authors [see attached article] mapped mutant clones in normal esophageal epithelium from nine donors (age range, 20 to 75 years). Somatic mutations accumulated with age and were caused presumably by dietary and endogenous metabolic mutational processes. Authors found strong positive selection of clones carrying mutations in 14 cancer genes — with tens to hundreds of clones per square centimeter.

In middle-aged and elderly donors, clones with cancer-associated mutations covered much of the esphageal epithelium, with NOTCH1 and TP53 gene mutations affecting 12 to 80% and 2 to 37% of cells, respectively. Unexpectedly, the prevalence of NOTCH1 mutations in normal esophagus was several times higher than that in esophageal cancers. Authors conclude that their findings have implications for our understanding of cancer and aging. For example, how can all these mutated cells/clones just be “sitting there”, rather than proceeding on to cause many more cancers?

Science 23 Nov 2o18; 362: 911–917 [article] & pp 893–894 [Editorial]

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