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

The DOI matches its Crossref record; 41 of the 42 references it cites were found in a registry or an index.

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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Crossref · 10.1038/s41586-018-0811-x

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Research works printed but not linked: 1

  1. Blokzijl, F., Janssen, R., Van Boxtel, R. & Cuppen, E. MutationalPatterns: an integrative R package for studying patterns in base substitution catalogues. Preprint at https://www.biorxiv.org/content/early/2016/08/30/071761 (2016).

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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
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
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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