P1.094. Cooporation of Aldh2 Deficiency and Tp53 Loss in Alcohol-Mediated Esophageal Squamous Field Cancerization

Abstract

Abstract Topic Esophageal Cancer: Esophageal Carcinogenesis Background Field cancerization in the upper aerodigestive tract is driven by alcohol, ALDH2 polymorphism, and TP53 mutation. However, animal models reflecting these factors are lacking. This study aims to clarify the combined involvement of alcohol consumption, Aldh2 dysfunction, and Trp53 loss in esophageal squamous cell carcinoma (ESCC) development. Methods We generated conditional p53-null Aldh2 mutant (Krt5-CreERT2;Trp53loxp/loxp; Aldh2ko/ko) mice featuring Aldh2-loss concurrent with Krt5-expressing epithelial-specific Trp53 deletion. Those mice were given either 10% ethanol or water, after tamoxifen administration to activate the Cre recombinase. We evaluated the development of squamous cell carcinogenesis histologically and genetically. Moreover, we assessed the effect of alcohol drinking volume on alcohol-mediated ESCC development. Then, induction of gene mutations in esophageal tissues by alcohol drinking was evaluated using Aldh2 knockout mice after drinking 10% ethanol for 3 months. Results Squamous cell carcinoma (SCC) occurred exclusively in TP53-null Aldh2ko/ko mice exposed to alcohol (15/18, 83%). Total alcohol consumption was significantly higher in mice that developed SCCs compared to those that did not within the same genotype. Targeted sequencing revealed the accumulation of genetic abnormalities, including Trp53 mutations, in the esophageal epithelium of Aldh2ko/ko mice following alcohol consumption. These findings indicate that alcohol exerts direct mutagenic effects on the esophageal epithelium, which, when combined with Aldh2 deficiency and Trp53 loss, synergistically drives the development of malignant lesions within the squamous field. Conclusion This study provides for the first time the evidence that alcohol drinking, Aldh2 dysfunction and Trp53 loss cooperate in squamous field cancerization. Alcohol consumption volume affects the SCCs development, even in the same genotype.