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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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“…(Genovese et al., 2014; Jaiswal et al., 2014), colon (Lee-Six et al., 2019), heart (Choudhury et al., 2022), oesophagus (Martincorena et al., 2018; Yokoyama et al., 2019), skin (Martincorena et al., 2015), lung (Yoshida et al., 2020), testes (Maher et al., 2018), small intestine (Wang et al.,…”
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“A guide RNA library was constructed against 23 genes whose mutants drive clonal expansion in normal human and mouse esophagus, 62 candidate drivers of esophageal cancer defined by the Intogen project and 50 essential genes 27,29,31,35,64,65 .”
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“Mutations in NOTCH1 were the most frequent event in normal bronchial, oesophageal and skin epithelium (squamous epithelia), whereas mutations in epigenetic modifiers DNMT3A and KMT2D were most common in haematopoietic tissue and urothelium respectively (22,23,26,28,35,53,56–63).”
BackgroundA pan-tissue survey of mosaic chromosomal alterations in 948 individuals
Gao, T., Kastriti, M. E., Ljungström, V., Heinzel, A., Tischler, A. S., Oberbauer, R. W., Loh, P., Adameyko, I. I., Park, P. J., & Kharchenko, P. V. (2023) · Nature Genetics · doi:10.1038/s41588-023-01537-1 · Cited by 24
“We also detected alterations on chromosomes 7, 8, 9 and 22, which are common in both PCC and adrenocortical carcinoma (ACC) (Fig.”
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ResultMitochondrial mutation, drift and selection during human development and ageingPreprint
Campbell, P. J., Chapman, M. S., Przybilla, M. J., Lawson, A. R. J., Mitchell, E., Dawson, K. J., Williams, N., Harvey, L. M. R., Ranzoni, A. M., Cvejic, A., et al. (2023) · Research Square · doi:10.21203/rs.3.rs-3083262/v1 · Cited by 26
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“We also noticed that NOTCH1 is frequently mutated in normal epithelia of the esophagus [17 ,18 ], and NOTCH1 mutations drive clonal expansion in the normal esophageal epithelium but impair tumor growth [19 ], suggesting the high prevalence of NOTCH1 , to some extent, might originate from mutations…”
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“The massive presence of oncogenic events in healthy tissues such as skin,[15] esophagus,[16] lung,[17] and many others[18] is another source of data leading us to consider alternatives”
BackgroundKelkka, T., Savola, P., Bhattacharya, D., Huuhtanen, J., Lönnberg, T., Kankainen, M., Paalanen, K., Tyster, M., Lepistö, M., Ellonen, P., et al. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.578848 · Cited by 19
“On the other hand, somatic mutations also accumulate in healthy tissues (9) with the highest mutation burdens reported thus far in the skin (10, 11), lung (12), and esophageal epithelium (13, 14).”
BackgroundNahta, R., & Castellino, R. C. (2020) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.114362 · Cited by 21
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“…chronic inflammation (Kakiuchi et al., 2020; Olafsson et al., 2020), bacterial infection (Lee- Six et al., 2019; Pleguezuelos- Manzano et al., 2020), and common lifestylerelated mutagens, such as sunlight, alcohol, and tobacco (Saini et al., 2021; Yokoyama et al., 2019; Yoshida et al., 2020).”
BackgroundZhao, Z., Cao, K., Watanabe, J., Philips, C. N., Zeidner, J. M., Ishi, Y., Wang, Q., Gold, S. R., Junkins, K., Bartom, E. T., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci169993 · Cited by 19
“Recent exome sequencing and whole-genome sequencing studies revealed that MLL3/4 and UTX mutations are not only found in tumor tissues but are also present in normal tissues such as esophagus (41, 42), endometrial epithelium (43), urothelium (27, 32), skin, and lung (44).”
Obesity-dependent selection of driver mutations in cancer
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BackgroundMutational selection in normal urothelium
Rozen, S. (2020) · Science · doi:10.1126/science.abe0955 · Cited by 19
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“9 Moreover, such driver-mutated clones were increased signi fi cantly in numbers with heavy smoking and drinking.”
BackgroundChen, X. L., Li, Y., Paiboonrungruang, C., Li, Y., Peters, H., Kist, R., & Xiong, Z. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23105589 · Cited by 18
Buhigas, C., Warren, A. Y., Leung, W., Whitaker, H. C., Luxton, H. J., Hawkins, S. F. C., Kay, J. D., Butler, A. P., Xu, Y., Woodcock, D. J., et al. (2022) · Molecular Cancer · doi:10.1186/s12943-022-01644-3 · Cited by 20
“Numerous reports of somatic mutations and clonal expansions in aging individuals are in agreement with this theory [5–8]: there is clear evidence that somatic mutations are present in morphologically normal skin [5, 9], brain [10], liver [11], oesophagus [6, 12], and colorectum [13] – in some cases affecting cancer-as…”
Choi, W.-I., Jeong, J., & Lee, C. W. (2019) · European Journal of Cancer · doi:10.1016/j.ejca.2019.09.010 · Cited by 19
Capp, J., & Frédéric Thomas, A. (2020) · iScience · doi:10.1016/j.isci.2020.101531 · Cited by 19
Cell competition, cooperation, and cancer
Marongiu, F., Cheri, S., & Laconi, E. (2021) · Neoplasia · doi:10.1016/j.neo.2021.08.001 · Cited by 19
Ageing and cancer: a research gap to fill
Solary, É., Abou‐Zeid, N., & Calvo, F. M. (2022) · Molecular Oncology · doi:10.1002/1878-0261.13222 · Cited by 18
Usui, G., Matsusaka, K., Huang, K. K., Zhu, F., Shinozaki, T., Fukuyo, M., Rahmutulla, B., Yogi, N., Okada, T., Minami, M., et al. (2023) · EBioMedicine · doi:10.1016/j.ebiom.2023.104844 · Cited by 17
“The methylation levels in gastric mucosae re fl ect the risk for future GN development and a shorter interval to incidence, drawing parallels to recent reports of somatic mutations 41,42 or copy number aberrations 43 accumulating in non-neoplastic tissues.”
Age-associated clonal B cells drive B cell lymphoma in mice
Castro, J. P., Shindyapina, A. V., Barbieri, A., Ying, K., Strelkova, O. S., Paulo, J. A., Tyshkovskiy, A., Meinl, R., Kerepesi, C., Petrashen, A. P., et al. (2024) · Nature Aging · doi:10.1038/s43587-024-00671-7 · Cited by 19
CHST15 promotes the proliferation of TE‑1 cells via multiple pathways in esophageal cancer
Wang, X., Cheng, G., Zhang, T., Deng, L., Xu, K., Xu, X. Y., Wang, W., Zhou, Z., Feng, Q., Chen, D., et al. (2019) · Oncology Reports · doi:10.3892/or.2019.7395 · Cited by 17
Melis, M., Zhang, T., Scognamiglio, T., & Gudas, L. J. (2020) · Carcinogenesis · doi:10.1093/carcin/bgaa019 · Cited by 17
New LncRNAs in Chronic Hepatitis C progression: from fibrosis to hepatocellular carcinoma
Ferrasi, A. C., Fernández, G. J., Grotto, R. M. T., Silva, G. F., Gonçalves, J., Costa, M. C., Enguita, F. J., & Pardini, M. I. D. M. C. (2020) · Scientific Reports · doi:10.1038/s41598-020-66881-2 · Cited by 17
Booka, E., Tsubosa, Y., Yokota, T., Mayanagi, S., Ishii, K., Urakami, K., Ohshima, K., Ohnami, S., Nagashima, T., & Yamaguchi, K. D. (2021) · Esophagus · doi:10.1007/s10388-021-00835-z · Cited by 17
Aging and Cancer: The Waning of Community Bonds
Laconi, E., Cheri, S., Fanti, M., & Marongiu, F. (2021) · Cells · doi:10.3390/cells10092269 · Cited by 18
“Thus, the human esophageal epithelium is progressively colonized by clonal populations carrying alterations in several genes, with a predominant presence of Notch1 mutants [97,100].”
BackgroundLineage tracing in human tissues
Gabbutt, C., Wright, N. A., Baker, A., Shibata, D. K., & Graham, T. A. (2022) · The Journal of Pathology · doi:10.1002/path.5911 · Cited by 16
Somatic Mutations in Normal Tissues: New Perspectives on Early Carcinogenesis
Herms, A., & Jones, P. H. (2023) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-061421-012447 · Cited by 18
Harris, K. L., Myers, M. B., McKim, K. L., Elespuru, R. K., & Parsons, B. L. (2019) · Environmental and Molecular Mutagenesis · doi:10.1002/em.22326 · Cited by 17
“2018), esophagus (Martincorena et al. 2018; Yokoyama et al. 2019), hematopoietic stem/progenitor cells (Welch et al.”
BackgroundFailure of immunosurveillance accelerates aging
Pérez-Lanzón, M., Zitvogel, L., & Kroemer, G. (2019) · OncoImmunology · doi:10.1080/2162402x.2019.1575117 · Cited by 17
Evolution and genomic signatures of spontaneous somatic mutation in Drosophila intestinal stem cellsPreprint
Riddiford, N., Siudeja, K., van den Beek, M., Boumard, B., & Bardin, A. J. (2021) · Genome Research · doi:10.1101/gr.268441.120 · Cited by 15
“Similarly, the mutations recently described to arise in aged normal cells and early-stage cancers represent the result of many years of selective pressure and mutational dynamics (Martincorena et al. 2015, 2018; Lee-Six et al. 2019; Moore et al. 2020; Yokoyama et al. 2019).”
BackgroundLi, Y. R., Kandyba, E. E., Halliwill, K. D., Delrosario, R., Tran, Q., Bayani, N., Wu, D., Mirzoeva, O. K., Reeves, M. Q., Islam, S. M. A., et al. (2025) · Cancer Discovery · doi:10.1158/2159-8290.cd-24-1379 · Cited by 16
“Affected tissues include skin (2), esophagus (3, 4), colon (5), liver (6), endometrium (7), and lung (8).”
The human brain through the lens of somatic mosaicism
Bizzotto, S. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1172469 · Cited by 17
Reversing pathological cell states: the road less travelled can extend the therapeutic horizon
Kholodenko, B. Ν., Kölch, W., & Rukhlenko, O. S. (2023) · Trends in Cell Biology · doi:10.1016/j.tcb.2023.04.004 · Cited by 19
Somatic mosaicism: implications for the cardiovascular system
Sano, S., Wang, Y., & Walsh, K. X. (2019) · European Heart Journal · doi:10.1093/eurheartj/ehz907 · Cited by 16
“In a related study, Yokoyama et al.(5) showed that lifestyle risk factors for oesophageal carcinoma (excessive alcohol consumption and smoking) were associated with increased clonal events within the normal epithelium, suggesting the existence of tissue-specific selective pressure on the development of these clones.”
BackgroundFeunteun, J., Ostyn, P., & Delaloge, S. (2022) · iScience · doi:10.1016/j.isci.2022.104217 · Cited by 16
“Furthermore, the accumulation of somatic mutations is most strongly associated with age, with additional effects of heavy smoking and alcohol consumption (Yokoyama et al., 2019).”
BackgroundA new era for understanding genetic evolution of multistep carcinogenesis
Shimada, S., & Tanaka, S. (2019) · Journal of Gastroenterology · doi:10.1007/s00535-019-01576-8 · Cited by 16
Sex and smoking bias in the selection of somatic mutations in human bladder
Calvet, F., Martínez-Illescas, R. B., Muiños, F., Tretiakova, M., Latorre-Esteves, E. S., Fredrickson, J., Andrianova, M. A., Pellegrini, S., Huber, A. R., Ramis-Zaldivar, J. E., et al. (2025) · Nature · doi:10.1038/s41586-025-09521-x · Cited by 21
“The reasons behind the wide heterogeneity in clonal landscape observed across normal human tissues from different people 7–12, 38, 39 and the potential role of known cancer risk factors are not The proposal of a pathway towards the study of natural saturation mutagenesis through ultradeep…”
Stem Cell–Derived Respiratory Epithelial Cell Cultures as Human Disease Models
Orr, J. C., & Hynds, R. E. (2021) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2020-0440tr · Cited by 15
Somatic genetic variation in healthy tissue and non-cancer diseases
Solís-Moruno, M., Batlle-Masó, L., Bonet, N., Aróstegui, J. I., & Casals, F. (2022) · European Journal of Human Genetics · doi:10.1038/s41431-022-01213-8 · Cited by 24
Testa, U., Castelli, G., & Pelosi, E. (2023) · Current Oncology · doi:10.3390/curroncol30010048 · Cited by 15
Decoding the obesity–cancer connection: lessons from preclinical models of pancreatic adenocarcinoma
Ruiz, C. F., Garcia, C. C., Jacox, J. B., Lawres, L., & Muzumdar, M. D. (2023) · Life Science Alliance · doi:10.26508/lsa.202302228 · Cited by 17
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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