Early TP53 alterations engage environmental exposures to promote gastric premalignancy in an integrative mouse model

Nat Genet. 2020 Feb;52(2):219-230. doi: 10.1038/s41588-019-0574-9. Epub 2020 Feb 5.


Somatic alterations in cancer genes are being detected in normal and premalignant tissue, thus placing greater emphasis on gene-environment interactions that enable disease phenotypes. By combining early genetic alterations with disease-relevant exposures, we developed an integrative mouse model to study gastric premalignancy. Deletion of Trp53 in gastric cells confers a selective advantage and promotes the development of dysplasia in the setting of dietary carcinogens. Organoid derivation from dysplastic lesions facilitated genomic, transcriptional and functional evaluation of gastric premalignancy. Cell cycle regulators, most notably Cdkn2a, were upregulated by p53 inactivation in gastric premalignancy, serving as a barrier to disease progression. Co-deletion of Cdkn2a and Trp53 in dysplastic gastric organoids promoted cancer phenotypes but also induced replication stress, exposing a susceptibility to DNA damage response inhibitors. These findings demonstrate the utility of mouse models that integrate genomic alterations with relevant exposures and highlight the importance of gene-environment interactions in shaping the premalignant state.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / pathology
  • Animals
  • Barrett Esophagus / genetics
  • Barrett Esophagus / pathology
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Environmental Exposure / adverse effects
  • Esophageal Neoplasms / genetics
  • Esophageal Neoplasms / pathology
  • Humans
  • Methylnitrosourea / toxicity
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Mutation
  • Neoplasms, Experimental / chemically induced
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / pathology
  • Organoids / pathology
  • Precancerous Conditions / genetics
  • Precancerous Conditions / pathology*
  • Stomach Neoplasms / drug therapy
  • Stomach Neoplasms / etiology*
  • Stomach Neoplasms / pathology
  • Tumor Suppressor Protein p53 / genetics*


  • Cdkn2a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • TP53 protein, human
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • Methylnitrosourea