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Cancer-associated mutations are common in normal human esophagus

October 18, 2018

Unexpectedly, a new study finds that cancer-associated genetic mutations are surprisingly common in aged, healthy esophageal epithelium tissue. The results further our understanding of cancer and aging and underscore how little is known about the mutational evolution within normal tissues, a process likely ubiquitous in the tissues of all living things. As people get older, they accumulate mutations in the healthy cells of normal tissues. Generally, these mutations accumulate passively and do not alter cell behavior. However, if a genetic alteration provides a mutant cell with a competitive edge, these cells become persistent mutant clones, which are thought to be the origin of cancer. Human skin, exposed to the powerful mutagenic power of the sun's light, is the most highly mutated normal tissue - nearly 25% of cells in the sun-exposed skin of middle-aged individuals carry cancer driver mutations. Despite its importance, the extent to which cells accumulate somatic mutations throughout life is poorly understood, particularly in tissues not exposed to mutagens like ultraviolet light. To explore the mutational burden of other tissues, Iñigo Martincorena and colleagues performed targeted gene sequencing of normal esophageal epithelium - a tissue-like skin, which lines the esophagus - from nine human donors ranging from 20 to 75 years of age. While the mutation rate was lower in the esophageal tissue than in skin, Martincorena et al. revealed a strong positive selection of cellular clones carrying mutations in 14 cancer-associated genes. According to the results, by middle age, over half of the esophageal epithelium tissue contained mutant clones. What's more, Martincorena et al. observed a high frequency of mutations in the cancer driver gene NOTCH1 in aged normal esophageal epithelium. These mutations were more common in normal cells than in esophageal cancer cells, suggesting that esophageal cancers are more likely to evolve from cells in epithelium without NOTCH1 mutations.
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American Association for the Advancement of Science

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