Cited by 629Cancer Genomics and DiagnosticsEsophageal Cancer Research and TreatmentEpigenetics and DNA Methylation

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Age-related remodelling of oesophageal epithelia by mutated cancer drivers

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, Amanuma, Yusuke, Ohashi, Shinya, Aoyama, Ikuo, Horimatsu, Takahiro, Miyamoto, Shin’ichi, Tsunoda, Shigeru, Sakai, Yoshiharu, Narahara, Maiko, Brown, J. B., Sato, Yoshitaka, Sawada, Genta, Mimori, Koshi, Minamiguchi, Sachiko, Haga, Hironori, Seno, Hiroshi, Miyano, Satoru, Makishima, Hideki, Muto, Manabu, Ogawa, Seishi·2019·Nature

DOI 10.1038/s41586-018-0811-x

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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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Basal extrusion of single‐oncogenic mutant cells induces dome‐like structures with altered microenvironments
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“In agreement with this observation, the average number of driver mutations per cell in normal esophagus was much lower than that in cancer cells, with one exception; the prevalence of NOTCH1 mutations in normal esophagus was several times higher than in esophageal cancers [4, 5].”
Background
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Targeted Next-Generation Sequencing of Flat Urothelial Lesions Reveals Putative Pathobiological Pathways, Potential Biomarkers, and Rational Therapeutic Targets
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Somatic mosaicism in the buccal mucosa reflects lifestyle and germline risk factors for esophageal squamous cell carcinoma
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Background
Time Trend of Upper Gastrointestinal Cancer Incidence in China from 1990 to 2019 and Analysis Using an Age–Period–Cohort Model
Lin, Y., Guo, Z., Huang, S., Ma, J., Xiang, Z., Huang, Y., Zhou, Y., & Chen, W. (2022) · Current Oncology · doi:10.3390/curroncol29100588 · Cited by 8
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Influential
Simulations reveal that different responses to cell crowding determine the expansion of p53 and Notch mutant clones in squamous epithelia
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Background
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“24 In older individuals, 40%–80% of the entire esophageal mucosa is remodeled by mutated clones.”
BackgroundInfluential
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Clinicopathological and molecular analyses of linearly expanded epithelial cells with β‐catenin alterations, “β‐catenin signature”, in the normal fallopian tube
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Background
Assessment of Clonal Expansion Using CarcSeq Measurement of Lung Cancer Driver Mutations and Correlation With Mouse Strain- and Sex-Related Incidence of Spontaneous Lung Neoplasia
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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
Publisher: Springer Science and Business Media LLC
Published: 2019-01-02
Volume: 565
Issue: 7739
Pages: 312-317
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/s41586-018-0811-x
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: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
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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Age-related remodelling of oesophageal epithelia by mutated cancer drivers

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