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p53 mutation in normal esophagus promotes multiple stages of carcinogenesis but is constrained by clonal competition

Author

Listed:
  • Kasumi Murai

    (Wellcome Sanger Institute)

  • Stefan Dentro

    (European Bioinformatics Institute
    DKFZ)

  • Swee Hoe Ong

    (Wellcome Sanger Institute)

  • Roshan Sood

    (Wellcome Sanger Institute)

  • David Fernandez-Antoran

    (Wellcome Sanger Institute
    Wellcome/Cancer Research UK Gurdon Institute, Henry Wellcome Building of Cancer and Developmental Biology)

  • Albert Herms

    (Wellcome Sanger Institute)

  • Vasiliki Kostiou

    (University College London)

  • Irina Abnizova

    (Wellcome Sanger Institute)

  • Benjamin A. Hall

    (University College London)

  • Moritz Gerstung

    (European Bioinformatics Institute
    DKFZ)

  • Philip H. Jones

    (Wellcome Sanger Institute
    University of Cambridge)

Abstract

Aging normal human oesophagus accumulates TP53 mutant clones. These are the origin of most oesophageal squamous carcinomas, in which biallelic TP53 disruption is almost universal. However, how p53 mutant clones expand and contribute to cancer development is unclear. Here we show that inducing the p53R245W mutant in single oesophageal progenitor cells in transgenic mice confers a proliferative advantage and clonal expansion but does not disrupt normal epithelial structure. Loss of the remaining p53 allele in mutant cells results in genomically unstable p53R245W/null epithelium with giant polyaneuploid cells and copy number altered clones. In carcinogenesis, p53 mutation does not initiate tumour formation, but tumours developing from areas with p53 mutation and LOH are larger and show extensive chromosomal instability compared to lesions arising in wild type epithelium. We conclude that p53 has distinct functions at different stages of carcinogenesis and that LOH within p53 mutant clones in normal epithelium is a critical step in malignant transformation.

Suggested Citation

  • Kasumi Murai & Stefan Dentro & Swee Hoe Ong & Roshan Sood & David Fernandez-Antoran & Albert Herms & Vasiliki Kostiou & Irina Abnizova & Benjamin A. Hall & Moritz Gerstung & Philip H. Jones, 2022. "p53 mutation in normal esophagus promotes multiple stages of carcinogenesis but is constrained by clonal competition," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33945-y
    DOI: 10.1038/s41467-022-33945-y
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    1. Jiaqi Liu & Lijun Dai & Qiang Wang & Chenghao Li & Zhichao Liu & Tongyang Gong & Hengyi Xu & Ziqi Jia & Wanyuan Sun & Xinyu Wang & Minyi Lu & Tongxuan Shang & Ning Zhao & Jiahui Cai & Zhigang Li & Hon, 2024. "Multimodal analysis of cfDNA methylomes for early detecting esophageal squamous cell carcinoma and precancerous lesions," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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