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Nat Genet DOI:10.1038/s41588-019-0574-9

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

Publication TypeJournal Article
Year of Publication2020
AuthorsSethi, NS, Kikuchi, O, Duronio, GN, Stachler, MD, McFarland, JM, Ferrer-Luna, R, Zhang, Y, Bao, C, Bronson, R, Patil, D, Sanchez-Vega, F, Bin Liu, J-, Sicinska, E, Lazaro, J-B, Ligon, KL, Beroukhim, R, Bass, AJ
JournalNat Genet
Volume52
Issue2
Pages219-230
Date Published2020 Feb
ISSN1546-1718
Abstract

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.

DOI10.1038/s41588-019-0574-9
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/32025000?dopt=Abstract

Alternate JournalNat. Genet.
PubMed ID32025000
PubMed Central IDPMC7031028
Grant ListDK120930 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /
K08 DK120930 / DK / NIDDK NIH HHS / United States
U54 CA163059 / CA / NCI NIH HHS / United States
P30 DK034854 / DK / NIDDK NIH HHS / United States
P50 CA127003 / CA / NCI NIH HHS / United States
P30 CA006516 / CA / NCI NIH HHS / United States
K08 DK109209 / DK / NIDDK NIH HHS / United States
P01 CA098101 / CA / NCI NIH HHS / United States