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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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“Instead, the discovery of widespread clonal expansions in ageing human tissues19,50–52 raises the possibility that some somatic mutations contribute to ageing by driving clonal expansions of functionally altered cells at a cost to the organism49,53,54.”
From Somatic mutation rates scale with lifespan across mammals (2022) · cites this paper as [52]
In the citing paper
“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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Of Barriers and Loops—How Evolution Limits Most Cancer Risks to Older Ages
Dominici, M. D., & DeGregori, J. V. (2026) · Cancer Discovery · doi:10.1158/2159-8290.cd-25-0779 · Cited by 3
Harnessing genomics for early cancer detection, risk stratification and prevention
Gu, M., Zhang, W. Z., Fitzgerald, R. C., Frankell, A. M., & Vassiliou, G. S. (2026) · Nature Genetics · doi:10.1038/s41588-026-02505-1 · Cited by 4
Beyond the Tumor Mass: From Initiating Clones to Overt Isocitrate Dehydrogenase-Mutant Gliomas
Park, J. W., Lee, J. H., & Kang, S. (2026) · DNA and Cell Biology · doi:10.1177/10445498261435336 · Cited by 2
“…in histologically normal tissues across multiple organs, including the esophagus, skin, colon, bladder, endometrium, and liver (Wijewardhane et al., 2021; Lawson et al., 2020; Moore et al., 2020; Brun-ner et al., 2019; Yokoyama et al., 2019; Lee-Six et al., 2019; Martincorena et al., 2018, 2015).”
Bile acids enrichment fuel tumor aerobic glycolysis and immune evasion via stabilizing FXR-RARα
Jiang, H., Xiong, W., Feng, Y., Li, X., Tan, J., & Zhang, Z. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1750358 · Cited by 2
A single-cell lens into the co-evolution of genotypes and phenotypes in cancer
Izzo, F., Prieto, T., Potenski, C. J., & Landau, D. A. (2026) · Nature reviews. Cancer · doi:10.1038/s41568-026-00970-8 · Cited by 2
“Studies in humans have shown that somatic mosaicism is a widespread phenomenon across multiple tissues including skin 4,5 , oral epithelium 80 , oesophagus 7,81 , blood 12 , colon 6 and bladder 10 , among others.”
iMutSig: a web application to identify the most similar mutational signature using shiny
Yang, Z. G., Pandey, P., Marjoram, P., & Siegmund, K. D. (2020) · F1000Research · doi:10.12688/f1000research.24435.1 · Cited by 2
Nature of spontaneously arising single base substitutions in normal cells
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“Whole-genome NGS in normal and precancerous regions of the esophageal epithelia (Yokoyama et al., 2019), skin (Martincorena et al.”
BackgroundHaematological malignancies in relatives of patients affected with myeloproliferative neoplasms
Vanni, D., Borsani, O., Nannya, Y., Sant’Antonio, E., Trotti, C., Casetti, I. C., Pietra, D., Gallì, A., Zibellini, S., Ferretti, V. V., et al. (2022) · eJHaem · doi:10.1002/jha2.425 · Cited by 2
Aging: Lifespan and the evolution of somatic mutation rates
Galeota-Sprung, B., & Sniegowski, P. (2022) · Current Biology · doi:10.1016/j.cub.2022.06.002 · Cited by 2
Religious fasting and the vascular health
Maslov, P. Z., Sabharwal, B., Ahmadi, A., Baliga, R. R., & Narula, J. (2022) · Indian Heart Journal · doi:10.1016/j.ihj.2022.07.005 · Cited by 2
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Potential to use of viral reverse transcriptase inhibitors in oncology
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Musangile, F. Y., Matsuzaki, I., Iwamoto, R., Sagan, K., Nishikawa, M., Mikasa, Y., Takahashi, Y., Higashine, R., Kojima, F., Hara, I., et al. (2024) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/s00428-024-03901-w · Cited by 3
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Clonal competition in a confined space
Naxerova, K. (2020) · Nature Genetics · doi:10.1038/s41588-020-0638-x · Cited by 2
Cell plasticity and genomic instability in cancer evolution
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Comprehensive mutational analysis of background mucosa in patients with Lugol‐voiding lesions
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Cellular and molecular mechanisms of breast cancer susceptibility
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Precision Nutrition and Cancer
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Mutation and clonal selection in the ageing oesophagus
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SCELLECTOR: ranking amplification bias in single cells using shallow sequencing
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The special issue on cancer and evolution: Lessons learned
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“…into ~ 100,000 oncogenically activated crypts in an adult) (Lee-Six et al., 2019), this number is much higher for the esophagus and the endometrium in older adults (Martincorena et al., 2018; Moore et al., 2020; Yokoyama et al., 2019), suggesting stronger selection against such clones in the colon.”
BackgroundSOD1 is a synthetic-lethal target in PPM1D-mutant leukemia cells
Zhang, L., Hsu, J. I., Braekeleer, E. D., Chen, C.-W., Patel, T. D., Martell, A. G., Guzman, A. G., Wohlan, K., Waldvogel, S. M., Urya, H., et al. (2023) · eLife · doi:10.1101/2023.08.31.555634 · Cited by 2
“However, the prevalence of PPM1D somatic mutations in other tissues such as the esophagus, suggests the need for further investigation (Yokoyama et al., 2019).”
BackgroundThe temporal evolution of cancer hallmarksPreprint
Gourmet, L. E., Ramazzoti, D., Mallick, P., Walker‐Samuel, S., & Zapata, L. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.01.21.576566 · Cited by 4
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Monitoring the rate and variability of somatic genomic alterations using long-read sequencing
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“The number of sSNVs is known to increase over a person lifetime, however, this has primarily been observed by analyzing the RNA of autopsy material 1 or DNA from biopsies 6,27 , or by laborious lab experiments 28 .”
The Primary Role of Noncoding RNA in the Pathogenesis of Cancer
Shah, A. (2025) · Genes · doi:10.3390/genes16070771 · Cited by 1
Metadata
- 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
- 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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