Somatic mutant clones colonize the human esophagus with age

By Iñigo Martincorena, J. Fowler, Agnieszka Wabik, A. Lawson, Federico Abascal, M. Hall, A. Cagan, K. Murai, Krishnaa T. A. Mahbubani, Michael R. Stratton and 5 more. Science, 2018

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The mutational burden of aging As people age, they accumulate somatic mutations in healthy cells. About 25% of cells in normal, sun-exposed skin harbor cancer driver mutations. What about tissues not exposed to powerful mutagens like ultraviolet light? Martincorena et al. performed targeted gene sequencing of normal esophageal epithelium from nine human donors of varying age (see the Perspective by Chanock). The mutation rate was lower in esophagus than in skin, but there was a strong positive selection of clones carrying mutations in 14 cancer-associated genes. By middle age, more than half of the esophageal epithelium was colonized by mutant clones. Interestingly, mutations in the cancer driver gene NOTCH1 were more common in normal esophageal epithelium than in esophageal cancer. Science, this issue p. 911; see also p. 893 Cancer-associated mutations are surprisingly common in normal esophageal epithelium from human donors. 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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/c26119e5f1657c8fab62c5c5b578947346b0de67

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Citations in the corpus

Clonal hematopoiesis in human aging and disease (2019, positive): “An equivalent state is also pervasive in the epithelium of skin (15) and esophagus (16, 17), suggesting that somatic mutation–driven clonal expansions may be a characteristic of aging in several tissues.”
DNA methylation aging clocks: challenges and recommendations (2019, background): “Increasing levels of somatic genetic mutation with age are now recognized [184, 185], leading to distinct clones, with potential pathological involvement even in nonmalignant age-related disease [186].”