An Integrative Mouse Model Reveals the Importance of CDKN2A in TP53-altered Gastric Premalignancy: whole exome sequencing. Mus musculus

TP53 mutations are the most common alteration in gastric adenocarcinoma, often occurring early in disease evolution prior to dysplasia. By combining early genetic alterations with disease-relevant exposures, we developed an integrative mouse model to study gastric premalignancy. Using this approach, we show that deletion of Trp53 in Lgr5+ or Mist1+ gastric cells confers a selective advantage in the setting of dietary carcinogenic exposure to promote metaplastic and dysplastic gastric lesions. Organoids derived from these models capture genomic, transcriptional, and functional features of Trp53-deleted gastric premalignancy. Transcriptional profiling of Trp53-deleted dysplastic gastric organoids revealed induction of interferon, stemness, and cell cycle regulation pathways, especially tumor suppressor Cdkn2a. CDKN2A and TP53 alterations significantly co-occur in human gastric cancer. Co-deletion of Cdkn2a and Trp53 in dysplastic gastric organoids promotes disease progression, induces replication stress, and confers susceptibility to DNA damage response pathway inhibition.We next piloted whole exome sequencing (WES) of these lesions using DNA from formalin-fixed paraffin embedded tissue.