Age-related remodeling of apparently normal esophageal epithelia by common cancer drivers. apparently normal esophageal epithelia

Esophageal squamous cell carcinoma develops in significant association with chronic exposure to drinking and smoking, frequently in a metachronous manner. To understand the genetic basis of clonal evolutions and their field effect contributions toward ESCC, we conducted multi-region sequencing in apparently normal non-dysplasia and dysplasia/cancer esophageal tissues. Mutations were identified in 96.9% of non-dysplasticnormal tissues, where NOTCH1, TP53 were significantly mutated. In dysplasia and cancer, NOTCH1 mutations were less frequent, whereas TP53 mutations and focal copy number lesions were dominant. Additional micrometer-resolution normal epitheliumnon-dysplasia analyses revealed bi-allelic NOTCH1 and TP53 mutations. The molecular profiles correlated strongly with alcohol- and smoking-related mutational signatures at all pathological stages, with an APOBEC-related signature predominant in cancer. ENon-dysplastic esophageal normal tissues of alcohol- and tobacco-consuming patients highlight genetically distinct non-cancerous clonal expansion.