Somatic mutant clones colonize the human esophagus with age
Open accessAbstract
The mutational burden of aging: As people age, they accumulate somatic mutations in healthy cells. About 25% of cells in normal, sun-exposed skin harbor cancer driver mutations. What about tissues not exposed to powerful mutagens like ultraviolet light? Martincorena et al. performed targeted gene sequencing of normal esophageal epithelium from nine human donors of varying age (see the Perspective by Chanock). The mutation rate was lower in esophagus than in skin, but there was a strong positive selection of clones carrying mutations in 14 cancer-associated genes. By middle age, more than half of the esophageal epithelium was colonized by mutant clones. Interestingly, mutations in the cancer driver gene NOTCH1 were more common in normal esophageal epithelium than in esophageal cancer. Science , this issue p. 911 ; see also p. 893
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Across most, if not all, tissues, after an initial expansion of the stem cell pool during early life, clonal heterogeneity tends to diminish over time.
“A consistent pattern has been observed across most, if not all, tissues: after an initial expansion of the stem cell pool during early life, clonal heterogeneity tends to diminish over time (Figure 1).17-24”
From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [22]
The Discussion reports that mutant clones colonize much of the esophageal epithelium with age, supporting age-related clonal expansion. The paper does not establish that clonal heterogeneity diminishes across most tissues, nor does it describe an initial expansion of the stem-cell pool in early life. (LLM, conf=0.83)
Experimental — accuracy not yet measuredSelected and more fit clones may share genomic events such as nonsynonymous mutations initially thought to be restricted to cancer.
“Interestingly, these selected and more fit clones may share genomic events such as nonsynonymous mutations initially thought to be restricted to cancer.17-24”
From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [22]
Clonal expansion has also been found in other human tissues, including skin, colon and oesophagus, and is thought to be a normal, possibly ubiquitous, process associated with ageing in all tissues, in particular those that experience significant cellular turnover.
“Clonal expansion has also been found in other human tissues, including skin, colon and oesophagus52–54, and is thought to be a normal, possibly ubiquitous, process that is associated with ageing in all tissues, in particular those that experience significant cellular turnover.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [53]
An equivalent state of somatic mutation-driven clonal expansions is pervasive in the epithelium of skin and esophagus, suggesting such expansions may be a characteristic of aging in several tissues.
“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 [15]
Tissue architecture constrains the extent of clonal expansion within tissues such as gut or skin epithelium to patches that are rarely larger than a few square millimeters, but there is no such spatial restriction on HSCs, which freely admix throughout the bone marrow and body.
“First, tissue architecture constrains the extent of clonal expansion within tissues such as gut or skin epithelium to patches that are rarely larger than a few square millimeters 15, but there is no such spatial restriction on HSCs, which freely admix throughout the bone marrow and body 78.”
From Clonal hematopoiesis in human aging and disease (2019) · cites this paper as [15]
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Cancer-associated mutations in endometriosis: shedding light on the pathogenesis and pathophysiology
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Self-citation
- Authors
- Martincorena, I., Fowler, J. C., Wabik, A., Lawson, A. R. J., Abascal, F., Hall, M. W. J., Cagan, A., Murai, K., Mahbubani, K., Stratton, M. R., Fitzgerald, R. C., Handford, P. A., Campbell, P. J., Saeb-Parsy, K., & Jones, P. H.
- Affiliations
- Wellcome Sanger Institute (GB)
- University of Cambridge (GB)
- University of Oxford (GB)
- Department of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge CB2 2QQ, UK.
- Corresponding author
- Martincorena, Iñigo
- Fowler, Joanna C.
- Jones, Philip H.
- ORCID
- Venue
- Science
- Published
- 2018-11-23
- Volume
- 362
- Issue
- 6417
- Pages
- 911-917
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC6298579
- OpenAlex
- W2897064819
- Cited by
- 1,113
- References
- 51
- Citations by year
- 2026: 101 · 2025: 111 · 2024: 116 · 2023: 149 · 2022: 167 · 2021: 167 · 2020: 164 · 2019: 128 · 2018: 8 · 2017: 1
- FWCI
- 35.57
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- Wellcome Trust (098051, 206194)
- Medical Research Council (Centenary Award)
- Cancer Research UK (CRUK C609/A17257, C57387/A21777)
- 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 › Genetics › Evolution and Genetic Dynamics
- Keywords
- somatic mutations, aging, esophageal epithelium, clonal expansion, mutational burden, Notch1, cancer driver genes, normal tissue
- MeSH terms
- Adult, Aged, Aging, Clone Cells, Esophageal Neoplasms, Esophagus, Female, Humans, Male, Middle Aged, Mutation, Selection, Genetic, Tumor Suppressor Protein p53, Receptor, Notch1, Young Adult
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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