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Cited by 121Developmental Biology and Gene RegulationCancer Genomics and DiagnosticsEsophageal Cancer Research and Treatment

Notch1 mutations drive clonal expansion in normal esophageal epithelium but impair tumor growth

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Abby, Emilie, Dentro, Stefan C., Hall, Michael W. J., Fowler, Joanna C., Ong, Swee Hoe, Sood, Roshan, Herms, Albert, Piedrafita, Gabriel +5 more·2023·Nature Genetics
DOI 10.1038/s41588-022-01280-zPMC PMC9925379
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Abstract

NOTCH1 mutant clones occupy the majority of normal human esophagus by middle age but are comparatively rare in esophageal cancers, suggesting NOTCH1 mutations drive clonal expansion but impede carcinogenesis. Here we test this hypothesis. Sequencing NOTCH1 mutant clones in aging human esophagus reveals frequent biallelic mutations that block NOTCH1 signaling. In mouse esophagus, heterozygous Notch1 mutation confers a competitive advantage over wild-type cells, an effect enhanced by loss of the second allele. Widespread Notch1 loss alters transcription but has minimal effects on the epithelial structure and cell dynamics. In a carcinogenesis model, Notch1 mutations were less prevalent in tumors than normal epithelium. Deletion of Notch1 reduced tumor growth, an effect recapitulated by anti-NOTCH1 antibody treatment. Notch1 null tumors showed reduced proliferation. We conclude that Notch1 mutations in normal epithelium are beneficial as wild-type Notch1 favors tumor expansion. NOTCH1 blockade may have therapeutic potential in preventing esophageal squamous cancer.

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  • In the esophagus, clonally expanding epithelial cells restrict tumorigenesis by outcompeting emerging cancer cells.

    “In the esophagus, clonally expanding epithelial cells restrict tumorigenesis by outcompeting emerging cancer cells (29, 30).”

    From Somatic mutations in TBX3 promote hepatic clonal expansion by accelerating VLDL secretion (2025) · cites this paper as [29]

    The Discussion (page not provided) says Notch1-mutant clones expand in normal esophageal epithelium by driving neighboring wild-type cells to differentiate. The paper also reports that Notch1 loss slows tumor growth, but it does not show that expanding epithelial clones restrict tumorigenesis by outcompeting emerging cancer cells. (LLM, conf=0.86)

    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 [17]

    The Discussion describes expanding NOTCH1-mutant clones that can dominate normal human esophagus, and the ‘Notch1 haploinsufficiency enables epithelial colonization’ section reports increasing mutant coverage with age. This supports age-related clonal dominance in esophageal epithelium, but the paper does not establish an initial expansion of the stem-cell pool during early life or the pattern across most tissues. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • 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 [17]

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Research works printed but not linked: 41

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Authors
Abby, E., Dentro, S. C., Hall, M. W. J., Fowler, J. C., Ong, S. H., Sood, R., Herms, A., Piedrafita, G., Abnizova, I., Siebel, C. W., Gerstung, M., Hall, B. A., & Jones, P. H.
Affiliations
  • Wellcome Sanger Institute (GB)
  • European Bioinformatics Institute (GB)
  • University of Cambridge (GB)
  • Universidad Complutense de Madrid (ES)
  • Genentech (US)
  • University College London (GB)
Corresponding author
Jones, Philip H.
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2023-01-19
Volume
55
Issue
2
Pages
232-245
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/s41588-022-01280-z
PMC
PMC9925379
OpenAlex
W4317502646
Cited by
121
References
45
Citations by year
2026: 31 · 2025: 31 · 2024: 42 · 2023: 16 · 2022: 1
FWCI
10.87
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Genetics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion, cc-by)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Apollo
  • Apollo (cc-by)
Funders
  • Cancer Research UK (C609/A27326, C609/A17257)
  • Wellcome Trust (296194, 098051)
  • RCUK | Medical Research Council (MR/S000216/1)
  • Royal Society (UF130039)
  • Ministry of Economy and Competitiveness | Agencia Estatal de Investigación (PID2020-116163GA-I00)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Health Sciences › Medicine › Surgery › Esophageal Cancer Research and Treatment
Keywords
NOTCH1 mutation, esophageal squamous cell carcinoma, clonal expansion, Notch signaling, tumor suppression, carcinogenesis, biallelic variants, tumor growth inhibition, esophageal epithelium, cell proliferation
MeSH terms
Animals, Epithelium, Esophageal Neoplasms, Humans, Middle Aged, Mutation, Mice, Receptor, Notch1, Carcinogenesis

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