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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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Hirata, H., Niida, A., Kakiuchi, N., Uchi, R., Sugimachi, K., Masuda, T., Saito, T., Kageyama, S., Motomura, Y., Ito, S., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-21-0653 · Cited by 37
Regulation of replication fork speed: Mechanisms and impact on genomic stability
Merchut‐Maya, J. M., Bártek, J., & Maya‐Mendoza, A. (2019) · DNA repair · doi:10.1016/j.dnarep.2019.102654 · Cited by 36
TP53 Mutations in Esophageal Squamous Cell Carcinoma
Zhong, L., Li, H., Chang, W., Ao, Y., Wen, Z., & Chen, Y. (2023) · Frontiers in Bioscience-Landmark · doi:10.31083/j.fbl2809219 · Cited by 34
Hirama, T., Tokita, S., Nakatsugawa, M., Murata, K., Nannya, Y., Matsuo, K., Inoko, H., Hirohashi, Y., Hashimoto, S., Ogawa, S., et al. (2021) · JCI Insight · doi:10.1172/jci.insight.146356 · Cited by 34
“We would like to thank M. Kudo and M. Hasegawa (Sapporo Medical University) for handling patient material and technical support for data processing.”
MethodInfluentialIsobe, T., Takagi, M., Sato‐Otsubo, A., Nishimura, A., Nagae, G., Yamagishi, C., Tamura, M., Tanaka, Y., Asada, S., Takeda, R., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-32266-4 · Cited by 36
Li, M., Zhang, Z., Wang, Q., Yan, Y., & Li, B. (2022) · Nature Communications · doi:10.1038/s41467-022-32962-1 · Cited by 33
Koyanagi, Y. N., Suzuki, E., Imoto, I., Kasugai, Y., Oze, I., Ugai, T., Iwase, M., Usui, Y., Kawakatsu, Y., Sawabe, M., et al. (2020) · Cancer Research · doi:10.1158/0008-5472.can-19-2685 · Cited by 33
Clonal hematopoiesis and VEXAS syndrome: survival of the fittest clones?
Kusne, Y. N., Fernandez, J. A., & Patnaik, M. M. (2021) · Seminars in Hematology · doi:10.1053/j.seminhematol.2021.10.004 · Cited by 34
Marongiu, F., & DeGregori, J. V. (2022) · Molecular Oncology · doi:10.1002/1878-0261.13275 · Cited by 38
Organismal metabolism regulates the expansion of oncogenic PIK3CA mutant clones in normal esophagus
Herms, A., Colom, B., Piedrafita, G., Kalogeropoulou, A., Banerjee, U., King, C., Abby, E., Murai, K., Caseda, I., Fernández‐Antorán, D., et al. (2024) · Nature Genetics · doi:10.1038/s41588-024-01891-8 · Cited by 33
“PIK3CA encodes the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K) and is recurrently mutated in normal human esophagus 1,4,8 .”
Progesterone from ovulatory menstrual cycles is an important cause of breast cancer
Bennink, H. J. T. C., Schultz, I. J., Schmidt, M., Jordan, V. C., Briggs, P., Egberts, J. F. M., Gemzell‐Danielsson, K., Kiesel, L., Kluivers, K. B., Krijgh, J., et al. (2023) · Breast Cancer Research · doi:10.1186/s13058-023-01661-0 · Cited by 34
Mutated clones are the new normal
Tomasetti, C. (2019) · Science · doi:10.1126/science.aax5525 · Cited by 30
Detection and Diagnostic Utilization of Cellular and Cell-Free Tumor DNA
Dudley, J. C., & Diehn, M. (2020) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-012419-032604 · Cited by 31
Cells with cancer‐associated mutations overtake our tissues as we age
Evans, E. J., & DeGregori, J. V. (2021) · Aging and Cancer · doi:10.1002/aac2.12037 · Cited by 35
Harada, H., Kikuchi, M., Asato, R., Hamaguchi, K., Tamaki, H., Mizuta, M., Hori, R., Kojima, T., Honda, K., Tsujimura, T., et al. (2023) · Head & Neck · doi:10.1002/hed.27398 · Cited by 31
Single-Cell Analysis of the Multicellular Ecosystem in Viral Carcinogenesis by HTLV-1
Koya, J., Saito, Y., Kameda, T., Kogure, Y., Yuasa, M., Nagasaki, J., McClure, M. B., Shingaki, S., Tabata, M., Tahira, Y., et al. (2021) · Blood Cancer Discovery · doi:10.1158/2643-3230.bcd-21-0044 · Cited by 31
Bao, C., Tourdot, R. W., Brunette, G. J., Stewart, C., Sun, L., Baba, H., Watanabe, M., Agoston, A. T., Jajoo, K., Davison, J. M., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-41805-6 · Cited by 42
“3-state (10) >3 state (17) amp (13) subclonal (2)”
Cellular survival over genomic perfection
Nik-Zainal, S., & Hall, B. A. (2019) · Science · doi:10.1126/science.aax8046 · Cited by 27
Tovy, A., Reyes, J. M., Gundry, M. C., Brunetti, L., Lee-Six, H., Petljak, M., Park, H. J., Guzman, A. G., Rosas, C., Jeffries, A. R., et al. (2020) · Cell Stem Cell · doi:10.1016/j.stem.2020.06.018 · Cited by 30
The role of host environment in cancer evolution
Solary, É., & Laplane, L. (2020) · Evolutionary Applications · doi:10.1111/eva.13039 · Cited by 33
“…were subsequently detected in a variety of other healthy tissues, including skin (Martincorena et al., 2015), esophagus (Martincorena et al., 2018; Yokoyama et al., 2019), liver (Brunner et al., 2019; Zhu et al., 2019), colon (Kakiuchi et al., 2020; Lee-Six et al., 2019; Nanki et al., 2020), lung…”
BackgroundNikaido, M., Kakiuchi, N., Miyamoto, S., Hirano, T., Takeuchi, Y., Funakoshi, T., Yokoyama, A., Ogasawara, T., Yamamoto, Y., Yamada, A., et al. (2021) · Gastric Cancer · doi:10.1007/s10120-021-01191-8 · Cited by 29
“Recent studies reported alcohol-related mutagenesis in gastric cancers in patients with alcohol consumption habit and ALDH2-defective alleles [12, 43].”
BackgroundMethodKeller, A., & Spits, C. (2021) · Cells · doi:10.3390/cells10113246 · Cited by 30
The landscape of genetic aberrations in myxofibrosarcoma
Takeuchi, Y., Yoshida, K., Halik, A., Kunitz, A., Suzuki, H., Kakiuchi, N., Shiozawa, Y., Yokoyama, A., Inoue, Y., Hirano, T., et al. (2022) · International Journal of Cancer · doi:10.1002/ijc.34051 · Cited by 30
A body map of somatic mutagenesis in morphologically normal human tissuesPreprint
Li, R., Di, L., Li, J., Fan, W., Liu, Y., Guo, W., Liu, W., Liu, L., Li, Q., Chen, L., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.11.30.403436 · Cited by 30
Inflammation-related parameter serve as prognostic biomarker in esophageal squamous cell carcinoma
Xu, X., & Jing, J. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.900305 · Cited by 29
Cell competition and cancer from Drosophila to mammals
Cong, B., & Cagan, R. L. (2024) · Oncogenesis · doi:10.1038/s41389-023-00505-y · Cited by 30
“Remarkably, many of these clones are functionally and phenotypically normal, with some even undergoing positive selection [3 – 7].”
BackgroundSomatic mutations in aging and disease
Ren, P., Zhang, J., & Vijg, J. (2024) · GeroScience · doi:10.1007/s11357-024-01113-3 · Cited by 30
“[80, 81, 83].”
Transient expansion of TP53 mutated clones in polycythemia vera patients treated with idasanutlin
Marcellino, B. K., Farnoud, N. R., Cassinat, B., Lü, M., Verger, E., McGovern, E. M., Patel, M. A., Medina-Martinez, J. S., Levine, M. F., Ossa, J. A., et al. (2020) · Blood Advances · doi:10.1182/bloodadvances.2020002379 · Cited by 31
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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