According to the findings of this study, the high frequency of NOTCH1 mutations in normal esophageal epitheliums, compared with the low frequency of NOTCH1 mutations in ESCC, suggests that these cancers predominantly originate from the epithelium without NOTCH1 mutations; in contrast, TP53 mutations observed at a lower frequency than NOTCH1 mutations in normal esophageal epitheliums, but present in the vast majority of ESCCs, suggest that these tumors originate from epithelial cells bearing these mutations [14]. Here, NOTCH1 is linked to esophageal squamous cell carcinoma.