Some of the mutations observed in normal esophageal epithelium occur at a frequency higher than that observed in ESCC; this condition is particularly evident for NOTCH1 mutations, but also for PPM1D (observed in 12.7% of normal epithelium compared with 0.58% in ESCC) and, to a lesser extent, for other genes, including NOTCH2, ZFP36L2, FAT1, NOTCH3, CHEK2 and PAX9 [17]. The gene discussed is NOTCH3; the disease is esophageal squamous cell carcinoma.