Age-related remodelling of oesophageal epithelia by mutated cancer drivers
Abstract
Clonal expansion in aged normal tissues has been implicated in the development of cancer. However, the chronology and risk dependence of the expansion are poorly understood. Here we intensively sequence 682 micro-scale oesophageal samples and show, in physiologically normal oesophageal epithelia, the progressive age-related expansion of clones that carry mutations in driver genes (predominantly NOTCH1), which is substantially accelerated by alcohol consumption and by smoking. Driver-mutated clones emerge multifocally from early childhood and increase their number and size with ageing, and ultimately replace almost the entire oesophageal epithelium in the extremely elderly. Compared with mutations in oesophageal cancer, there is a marked overrepresentation of NOTCH1 and PPM1D mutations in physiologically normal oesophageal epithelia; these mutations can be acquired before late adolescence (as early as early infancy) and significantly increase in number with heavy smoking and drinking. The remodelling of the oesophageal epithelium by driver-mutated clones is an inevitable consequence of normal ageing, which-depending on lifestyle risks-may affect cancer development.
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An equivalent state of somatic mutation-driven clonal expansions is pervasive in the epithelium of skin and esophagus, suggesting such expansions may be a characteristic of aging in several tissues.
“An equivalent state is also pervasive in the epithelium of skin 14 and esophagus 15,16, suggesting that somatic mutation-driven clonal expansions may be a characteristic of aging in several tissues.”
From Clonal hematopoiesis in human aging and disease (2019) · cites this paper as [16]
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BackgroundThe Role of TP53 in Adaptation and Evolution
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BackgroundResultThe somatic mutation landscape of the human body
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On the Origin of ATP Synthesis in Cancer
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BackgroundNotch1 mutations drive clonal expansion in normal esophageal epithelium but impair tumor growth
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BackgroundClonal hematopoiesis, somatic mosaicism, and age-associated disease
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BackgroundThe Origin and Immune Recognition of Tumor-Specific Antigens
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Epithelial defense against cancer (EDAC)
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Splicing Factor SRSF1 Promotes Pancreatitis and KRASG12D-Mediated Pancreatic Cancer
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- Authors
- Yokoyama, A., Kakiuchi, N., Yoshizato, T., Nannya, Y., Suzuki, H., Takeuchi, Y., Shiozawa, Y., Sato, Y., Aoki, K., Kim, S. K., Fujii, Y., Yoshida, K., Kataoka, K., Nakagawa, M. M., Inoue, Y., Hirano, T., Shiraishi, Y., Chiba, K., Tanaka, H., Sanada, M., Nishikawa, Y., Amanuma, Y., Ohashi, S., Aoyama, I., Horimatsu, T., Miyamoto, S., Tsunoda, S., Sakai, Y., Narahara, M., Brown, J. B., Sato, Y., Sawada, G., Mimori, K., Minamiguchi, S., Haga, H., Seno, H., Miyano, S., Makishima, H., Muto, M., & Ogawa, S.
- Affiliations
- Kyoto University (JP)
- Institute of Medical Science, The University of Tokyo (JP)
- Nagoya Medical Center (JP)
- Kyoto University Hospital (JP)
- McGill University (CA)
- Kyushu University Beppu Hospital (JP)
- Corresponding author
- Ogawa, Seishi
- ORCID
- Yokoyama, Akira
- Kakiuchi, Nobuyuki
- Yoshizato, Tetsuichi
- Nannya, Yasuhito
- Suzuki, Hiromichi
- Takeuchi, Yasuhide
- Shiozawa, Yusuke
- Sato, Yusuke
- Aoki, Kosuke
- Kim, Soo Ki
- Fujii, Yoichi
- Yoshida, Kenichi
- Kataoka, Keisuke
- Nakagawa, Masahiro M.
- Inoue, Yoshikage
- Hirano, Tomonori
- Shiraishi, Yuichi
- Chiba, Kenichi
- Tanaka, Hiroko
- Sanada, Masashi
- Nishikawa, Yoshitaka
- Ohashi, Shinya
- Horimatsu, Takahiro
- Miyamoto, Shin’ichi
- Tsunoda, Shigeru
- Sakai, Yoshiharu
- Sato, Yoshitaka
- Mimori, Koshi
- Minamiguchi, Sachiko
- Haga, Hironori
- Seno, Hiroshi
- Miyano, Satoru
- Makishima, Hideki
- Muto, Manabu
- Ogawa, Seishi
- Venue
- Nature
- Published
- 2019-01-02
- Volume
- 565
- Issue
- 7739
- Pages
- 312-317
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2905667684
- Cited by
- 628
- References
- 42
- Citations by year
- 2026: 43 · 2025: 54 · 2024: 64 · 2023: 97 · 2022: 109 · 2021: 95 · 2020: 106 · 2019: 58 · 2018: 1
- FWCI
- 19.72
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Kyoto University Research Information Repository (Kyoto University) (submittedVersion)
- Funders
- Ministry of Education, Science and Technology
- Japan Society for the Promotion of Science (18H02692, 15H05791, 15H05912, 17K19595, 15H05909)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Surgery › Esophageal Cancer Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- esophageal epithelium, clonal expansion, driver mutations, Notch1, PPM1D, aging, esophageal squamous cell carcinoma, alcohol consumption, smoking, cancer risk, single-cell sequencing
- MeSH terms
- Mutation Accumulation, Protein Phosphatase 2C, Adolescent, Adult, Aged, Aged, 80 and over, Aging, Alcohol Drinking, Biopsy, Cell Count, Cell Transformation, Neoplastic, Child, Child, Preschool, Clone Cells, Epithelium, Esophageal Neoplasms, Female, Humans, Infant, Life Style, Male, Middle Aged, Mutation, Precancerous Conditions, Risk Factors, Smoking, Genome, Human, Sequence Analysis, DNA, Evolution, Molecular, Receptor, Notch1, Young Adult, DNA Copy Number Variations, Single-Cell Analysis, Gene-Environment Interaction
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