EGF and esophageal squamous cell carcinoma: This activation triggers the transcription of downstream target genes, including HES1, HES4, HEY1, and MYC. 18,19 Mutations in NOTCH1 are mainly concentrated in the extracellular EGF-like domain, impairing ligand binding and leading to the loss of Notch signaling function.15 Although NOTCH1 mutations occur in nearly 20% of ESCC cases, a larger proportion of patients without mutations still exhibit functional Notch signaling in their tumors.