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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Hussein, S. E., Evans, A. G., Fitzsimmons, J. M., Leong, N., Buldo, M., Segal, J. P., Jajosky, A. N., Rothberg, P. G., Liesveld, J. L., & Oltvai, Z. N. (2023) · Molecular Case Studies · doi:10.1101/mcs.a006241
“The fact that the effect of various oncogenic mutations can be efficiently buffered to maintain normal tissue homeostasis (i.e., allostasis) has been well-established (Martincorena et al. 2015, 2018; Yokoyama et al. 2019).”
Background
Do ‘cancer mutations’ stand only for cancer? Translational and clinical implications
Mentis, A. A., Papavassiliou, K. A., & Papavassiliou, A. G. (2023) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2023.06.004
Gamétogenèse invitro
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SOD1 is a synthetic lethal target in PPM1D-mutant leukemia cellsPreprint
Zhang, L., Hsu, J. I., Braekeleer, E. D., Chen, C.-W., Patel, T. D., Urya, H., Guzman, A. G., Martell, A. G., Waldvogel, S. M., Tovy, A., et al. (2023) · eLife · doi:10.7554/elife.91611.1
Emergence of multiple revertant keratinocyte clones in a patient with KID syndrome
Ishida, Y., Murata, T., Kakiuchi, N., Ogawa, S., & Kabashima, K. (2023) · Journal of the European Academy of Dermatology and Venereology · doi:10.1111/jdv.19595
Bile acids enrichment supports tumor aerobic glycolysis and establishes immunosuppressive microenvironmentPreprint
Zhang, Z., Jiang, H., Li, X., Tan, J., & Wu, R. (2023) · Research Square · doi:10.21203/rs.3.rs-2669331/v1
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Insights into genetic predisposition of somatic cancers
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2. Crohn's Lesions in Normal Tissue
Ogawa, S. (2023) · Nihon Naika Gakkai Zasshi · doi:10.2169/naika.112.81a
SOD1 is a synthetic lethal target in PPM1D-mutant leukemia cellsPreprint
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. (2024) · eLife · doi:10.7554/elife.91611.2
Additional file 2 of FBXW7 loss of function promotes esophageal squamous cell carcinoma progression via elevating MAP4 and ERK phosphorylation
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Comprehensive Understanding of Esophageal Carcinogenesis Mechanisms Due to Alcohol and Other Risk Factors
Mimori, K. (2024) · Nihon Kikan Shokudoka Gakkai Kaiho · doi:10.2468/jbes.75.67
Current advances on single or multi-omics analysis of esophageal cancer
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2. Crohn's Lesions in Normal Tissue
Ogawa, S. (2023) · Nihon Naika Gakkai Zasshi · doi:10.2169/naika.112.1507
The temporal evolution of cancer hallmarksPreprint
Zapata, L., Gourmet, L. E., Lam, J. M., Ramazzotti, D., Pennycuick, A., Mallick, P., & Walker‐Samuel, S. (2024) · Research Square · doi:10.21203/rs.3.rs-5499335/v1
A Spotlight on Oxidative Metabolism in Oncogenic Transformation and Cell Competition
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A Multimodal Machine Learning Model Integrating Ultrasound and Serological Biomarkers for Non-Invasive Prediction of Gallbladder Polyp Malignancy: Development, Validation, and Clinical TranslationPreprint
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Microbiota-Derived Bile Acids Fuel Tumor Aerobic Glycolysis and Immune Evasion Via Fxr-Rarα SignalingPreprint
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“[28,29] Elevated levels of CA19-9, a serological marker commonly associated with pancreatobiliary malignancies, also contributed significantly to the model’s predictive power.”
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Ohashi, T., Okimoto, K., Kaneko, T., Akizue, N., Hirotsu, Y., Amemiya, K., Krosugi, A., Ishikawa, T., Ohta, Y., Taida, T., et al. (2025) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.70129
Site-specific prevalence of the NFE2L2 mutation in esophageal squamous cell carcinoma
Chida, A., Hayashi, H., Ishida, N., So, E., Kishimoto, S., Horie, S., Tsugaru, K., Matsuda, S., Kawakubo, H., Nishihara, H., et al. (2025) · International Journal of Clinical Oncology · doi:10.1007/s10147-025-02908-w
“Prior studies have shown high mutation rates of NFE2L2 in ESCC tissue but not in normal esophageal epithelium [16].”
Additional file 1 of Mutational concordance analysis provides supportive information for double cancer diagnosis
Hatakeyama, K., Nagashima, T., Notsu, A., Ohshima, K., Ohnami, S., Ohnami, S., Shimoda, Y., Naruoka, A., Maruyama, K., Iizuka, A., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14067957
Additional file 2 of Mutational concordance analysis provides supportive information for double cancer diagnosis
Hatakeyama, K., Nagashima, T., Notsu, A., Ohshima, K., Ohnami, S., Ohnami, S., Shimoda, Y., Naruoka, A., Maruyama, K., Iizuka, A., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14067960
Additional file 1 of Pre-operative clonal hematopoiesis is related to adverse outcome in lung cancer after adjuvant therapy
Yun, J. K., Kim, S., An, H., Lee, G. D., Kim, H. R., Kim, Y.-H., Kim, D. K., Park, S.-I., Choi, S., & Koh, Y. (2023) · Figshare · doi:10.6084/m9.figshare.24797878
Additional file 1 of FBXW7 loss of function promotes esophageal squamous cell carcinoma progression via elevating MAP4 and ERK phosphorylation
Pan, Y., Liu, J., Gao, Y., Guo, Y., Wang, C., Liang, Z., Wu, M., Qian, Y., Li, Y., Shen, J., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22624969
Additional file 2 of Pre-operative clonal hematopoiesis is related to adverse outcome in lung cancer after adjuvant therapy
Yun, J. K., Kim, S., An, H., Lee, G. D., Kim, H. R., Kim, Y.-H., Kim, D. K., Park, S.-I., Choi, S., & Koh, Y. (2024) · Figshare · doi:10.6084/m9.figshare.24798085
Additional file 10 of Comparative assessment of genes driving cancer and somatic evolution in non-cancer tissues: an update of the Network of Cancer Genes (NCG) resource
Dreßler, L., Bortolomeazzi, M., Keddar, M. R., Mišetić, H., Giulia, S., Acha‐Sagredo, A., Montorsi, L., Wijewardhane, N., Repana, D., Nulsen, J., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19068666
Additional file 1 of SCELLECTOR: ranking amplification bias in single cells using shallow sequencing
Sarangi, V., Jourdon, A., Bae, T., Panda, A., Vaccarino, F., & Abyzov, A. S. (2020) · Figshare · doi:10.6084/m9.figshare.13233081
Additional file 2 of Comparative assessment of genes driving cancer and somatic evolution in non-cancer tissues: an update of the Network of Cancer Genes (NCG) resource
Dreßler, L., Bortolomeazzi, M., Keddar, M. R., Mišetić, H., Sartini, G., Acha‐Sagredo, A., Montorsi, L., Wijewardhane, N., Repana, D., Nulsen, J., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19068675
Additional file 2 of The architecture of clonal expansions in morphologically normal tissue from cancerous and non-cancerous prostates
Buhigas, C., Warren, A. Y., Leung, W.-K., Whitaker, H. C., Luxton, H. J., Hawkins, S. F. C., Kay, J. D., Butler, A. P., Xu, Y., Woodcock, D. J., et al. (2022) · Figshare · doi:10.6084/m9.figshare.21185570
The interplay between dormant mutated cells and tumor promotion by chronic tissue damage in determining cancer riskPreprint
Li, Y. R., Kandyba, E. E., Halliwill, K. D., Delrosario, R., Tran, Q., Bayani, N., Wu, D., Mirzoeva, O. K., Reeves, M. M., Islam, M., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.01.24.577147
“First, abundant mutations have been found by deep sequencing of DNA in multiple normal human tissues including skin(11) esophagus(12,13) colon(14), liver(15) endometrium(16) and lung(17) The number of cells carrying these mutations is very high in the skin and oesophagus, where as many as 70-80% of…”
Background
Genetic risk stratification and preventive strategies for double primary HNSCC and ESCC: a single-center cohort study
Naito, S., Umezu, T., Yamaguchi, H., Muramatsu, T., Kagawa, Y., Morise, T., Yamauchi, Y., Okamoto, I., Fukuzawa, M., Tsukahara, K., et al. (2026) · Esophagus · doi:10.1007/s10388-026-01187-2
“In patients with double cancers and LVLs, smoking was a dominant risk factor, and esophageal mucosal remodeling with age may have exacerbated smoking-induced damage [28].”
Non-Coding RNA: Architects of Cellular Complexity and Agents of Malignancy
Shah, A. (2026) · Genes · doi:10.3390/genes17030304
Development of an error-corrected next-generation sequencing method for the quantification of hotspot cancer driver mutations
Harris, K. L. (2026) · Cell Signaling · doi:10.46439/signaling.4.093
Polyclonal evolution of lymphoproliferative disorders in XLP1
Tomomasa, D., Nishimura, A., Yoshida, K., Namikawa, Y., Kim, D. R., Sakata, N., Sakamoto, K., Taga, T., Sakai, Y., Ikawa, Y., et al. (2026) · Journal of Human Immunity · doi:10.70962/jhi.20250202
“Somatic mutations were identified using the Gnomon pipeline, with sequencing data of non-paired normal tissues used as controls (26).”

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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