Early TP53 alterations engage environmental exposures to promote gastric premalignancy in an integrative mouse model.
Nilay S SethiOsamu KikuchiGina N DuronioMatthew D StachlerJames M McFarlandRuben Ferrer-LunaYanxi ZhangChunyang BaoRoderick BronsonDeepa PatilFrancisco Sanchez-VegaJie-Bin LiuEwa SicinskaJean-Bernard LazaroKeith L LigonRameen BeroukhimAdam J BassPublished in: Nature genetics (2020)
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.
Keyphrases
- mouse model
- copy number
- cell cycle
- genome wide
- dna damage response
- air pollution
- papillary thyroid
- cell proliferation
- gene expression
- squamous cell carcinoma
- transcription factor
- dna methylation
- oxidative stress
- high glucose
- dna damage
- cell cycle arrest
- squamous cell
- young adults
- diabetic rats
- risk assessment
- endothelial cells
- genome wide analysis
- drug induced
- human health