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Scientists at the MRC Cancer Unit of the Wellcome Sanger Institute and other departments of the University of Cambridge discovered that healthy esophageal tissue accumulates very high numbers of mutations with age, to the point that, by the time middle age is reached, it is likely to contain more cells with a particular mutation than cells without it [1].

Abstract

The extent to which cells in normal tissues accumulate mutations throughout life is poorly understood. Some mutant cells expand into clones that can be detected by genome sequencing. We mapped mutant clones in normal esophageal epithelium from nine donors (age range, 20 to 75 years). Somatic mutations accumulated with age and were caused mainly by intrinsic mutational processes. We 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 epithelium, with NOTCH1 and TP53 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 in esophageal cancers. These findings have implications for our understanding of cancer and aging.

The esophagus and esophageal cancer

The esophagus, which connects the throat to the stomach, may be affected primarily by two different types of cancer: squamous cell carcinoma, which affects the epithelial cells lining the organ, and adenocarcinoma, which affects the glandular cells located in the lower part of the esophagus. Unfortunately, the prognosis for this type of cancer is rather poor; the disease may progress without symptoms until an advanced stage, which causes many diagnoses to come rather late. Consequently, the prognosis is also usually poor; risk factors include tobacco smoking, alcohol use, and exposure to carcinogens that may be present in processed or barbecued meats.

The study

The researchers sampled healthy esophageal tissue, free of any cancer sign, from nine people between 20 and 75 years of age who were not taking any medications for esophagus-related problems; thanks to genome sequencing, the scientists found out that the tissue from volunteers in their 20s carried up to several hundred mutations, and the figure rose to over 2,000 mutations per cell for older individuals.

The study uncovered new information about mutations of two genes that are related to cancer. The gene for tumor protein 53 (TP53), more commonly known as p53, is found to mutate in nearly all esophageal cancers, and the researchers found that it was mutated in 5 to 10 percent of normal cells donated by the volunteers. p53 is often called “the guardian of the genome” for its role as a tumor suppressor and promoter of genomic stability.

Surprisingly, the NOTCH1 gene, which controls cell division, was found to be mutated in normal cells far more commonly than in cancer cells. NOTCH1 is generally assumed to be a driver of esophageal squamous cell carcinomas, since it is found to be mutated in about 10% of cases; however, as the researchers found that up to 80% of normal tissue from middle-aged volunteers exhibits the mutation, this notion might have to be reconsidered.

These data led the scientists to hypothesize that esophageal cancer may be more likely to develop from cells that have p53 mutations but do not have NOTCH1 mutations, even though they acknowledge that larger cohorts of subjects will have to be examined before anything can be said with certainty.

Conclusion

The researchers hope that this study, and others like it, may help finding clues to identify higher-risk patients in time and therefore to develop diagnostics that may detect esophageal cancer before it manifests clinically—that is, when it’s usually too late. However, the path to such diagnostics is still long.

Literature

[1] Martincorena, I., Fowler, J. C., Wabik, A., Lawson, A. R. J., Abascal, F., Hall, M. W. J., … Jones, P. H. (2018). Somatic mutant clones colonize the human esophagus with age. Science, eaau3879.

CategoryNews, Research
About the author

Nicola Bagalà

Nicola is a bit of a jack of all trades—a holder of an M.Sc. in mathematics; an amateur programmer; a hobbyist at novel writing, piano and art; and, of course, a passionate life extensionist. After his interest in the science of undoing aging arose in 2011, he gradually shifted from quiet supporter to active advocate in 2015, first launching his advocacy blog Rejuvenaction before eventually joining LEAF. These years in the field sparked an interest in molecular biology, which he actively studies. Other subjects he loves to discuss to no end are cosmology, artificial intelligence, and many others—far too many for a currently normal lifespan, which is one of the reasons he’s into life extension.
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