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Cited by 57Cancer Genomics and DiagnosticsGenetic factors in colorectal cancerEpigenetics and DNA Methylation

The somatic mutation landscape of normal gastric epithelium

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Coorens, Tim H. H., Collord, Grace, Jung, Hyungchul, Wang, Yichen, Moore, Luiza, Hooks, Yvette, Mahbubani, Krishnaa, Law, Simon Y. K. +7 more·2025·Nature
DOI 10.1038/s41586-025-08708-6PMC PMC11981919

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Abstract

The landscapes of somatic mutation in normal cells inform us about the processes of mutation and selection operative throughout life, providing insight into normal ageing and the earliest stages of cancer development 1 . Here, by whole-genome sequencing of 238 microdissections 2 from 30 individuals, including 18 with gastric cancer, we elucidate the developmental trajectories of normal and malignant gastric epithelium. We find that gastric glands are units of monoclonal cell populations that accrue roughly 28 somatic single-nucleotide variants per year, predominantly attributable to endogenous mutational processes. In individuals with gastric cancer, metaplastic glands often show elevated mutation burdens due to acceleration of mutational processes linked to proliferation and oxidative damage. Unusually for normal cells, gastric epithelial cells often carry recurrent trisomies of specific chromosomes, which are highly enriched in a subset of individuals. Surveying 829 polyclonal gastric microbiopsies by targeted sequencing, we find somatic ‘driver’ mutations in a distinctive repertoire of known cancer genes, including ARID1A , ARID1B , ARID2 , CTNNB1 and KDM6A . The prevalence of mutant clones increases with age to occupy roughly 8% of the gastric epithelial lining by age 60 years and is significantly increased by the presence of severe chronic inflammation. Our findings provide insights into intrinsic and extrinsic influences on somatic evolution in the gastric epithelium in healthy, precancerous and malignant states.

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  • Selected 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 [19]

    The “Driver mutations in gastric glands” section reports positive selection in normal gastric glands for several genes also frequently mutated in gastric cancer, as well as mutations at known cancer-gene hotspots. This supports the claim that selected normal clones can carry cancer-associated mutations, including nonsynonymous ones. Our copy does not establish that these mutations were initially thought to be restricted to cancer (page numbers unavailable). (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • 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 [19]

    The ‘Mutation rates of gastric epithelium’ section (page not provided) says gastric glands start as polyclonal units and drift toward monoclonality, supporting declining clonal heterogeneity in that tissue. It does not establish an initial early-life expansion of the stem cell pool or the same pattern across most tissues. (LLM, conf=0.84)

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Authors
Coorens, T. H. H., Collord, G., Jung, H., Wang, Y., Moore, L., Hooks, Y., Mahbubani, K., Law, S. Y. K., Yan, H. H. N., Yuen, S. T., Saeb-Parsy, K., Campbell, P. J., Martincorena, I., Leung, S. Y., & Stratton, M. R.
Affiliations
  • Broad Institute (US)
  • University College Hospital (GB)
  • Wellcome Sanger Institute (GB)
  • University of Cambridge (GB)
  • Queen Mary Hospital (CN)
  • Wellcome/MRC Cambridge Stem Cell Institute (GB)
Corresponding author
  • Coorens, Tim H. H.
  • Leung, Suet Yi
  • Stratton, Michael R.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2025-03-19
Volume
640
Issue
8058
Pages
418-426
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-025-08708-6
PMC
PMC11981919
OpenAlex
W4408614211
Cited by
57
References
5
Citations by year
2026: 37 · 2025: 19 · 2024: 1
FWCI
25.03
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
Funders
Wellcome Trust
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
somatic mutations, gastric epithelium, gastric cancer, metaplasia, endogenous mutagenesis, oxidative damage, trisomy, somatic driver mutations, ARID1A, ARID1B, ARID2, CTNNB1, KDM6A, chronic inflammation, aging, precancerous lesions, clonal evolution
MeSH terms
Whole Genome Sequencing, Adult, Aged, Aged, 80 and over, Aging, Clone Cells, DNA-Binding Proteins, Epithelial Cells, Female, Gastric Mucosa, Humans, Inflammation, Male, Metaplasia, Middle Aged, Mutation, Stomach Neoplasms, Transcription Factors, Trisomy, Cohort Studies, Polymorphism, Single Nucleotide, beta Catenin, Mutation Rate

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