In this study, NFE2L2, NOTCH1, EP100, FAT1, NFKBIA, KAT6A, and KMT2D were the most mutated genes in ESCC; SMAD4, KRAS, ARID1A, and DYNC2H1 were the most mutated genes in EAC, similar to the literature. This evidence concerns the gene SMAD4 and esophageal squamous cell carcinoma.