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.
journal_name
Nat Genetjournal_title
Nature geneticsauthors
Sethi NS,Kikuchi O,Duronio GN,Stachler MD,McFarland JM,Ferrer-Luna R,Zhang Y,Bao C,Bronson R,Patil D,Sanchez-Vega F,Liu JB,Sicinska E,Lazaro JB,Ligon KL,Beroukhim R,Bass AJdoi
10.1038/s41588-019-0574-9subject
Has Abstractpub_date
2020-02-01 00:00:00pages
219-230issue
2eissn
1061-4036issn
1546-1718pii
10.1038/s41588-019-0574-9journal_volume
52pub_type
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