NOTCH1 and esophageal squamous cell carcinoma: Since most NOTCH1 mutations in ESCC occur in the EGF-like domain, which impedes its ligand from binding to it, leading to Notch signaling inactivation,15 one may expect that NOTCH1-mutated cells will remain in aged normal esophagus but be largely eliminated in ESCC tumors due to the angiogenetic need of cancer.