Somatic alterations in cancer genes are now being detected in normal and premalignant tissue, placing greater emphasis on gene-environment interactions that enable malignant progression. The chromosomal instability subtype of gastrointestinal cancers is molded by environmental and cellular context. Through a comparative molecular analysis, we found that adenocarcinomas arising from the lower esophagus and stomach manifest more fragmented aneuploid genomes relative to those originating from the colorectum. To study gene-environment interactions that shape this molecular architecture, we developed an integrative mouse model of gastric premalignancy that combines early genetic alterations with disease-relevant exposures. Organoid derivation from dysplastic lesions facilitated genomic, transcriptional, and functional evaluation of gastric premalignancy. Our 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.
(Refreshments will be served at 3:45 pm)