NOTCH1 and esophageal squamous cell carcinoma: Similarly, among esophageal squamous cell carcinomas (ESSCs), non-synonymous mutations in the NOTCH1 gene are far more common than synonymous mutations, indicating strong positive selection and therefore implicating NOTCH1 mutations in ESSC development by standard methods; yet refuting that implication, NOTCH1 mutations are even more frequent in the normal esophageal epithelium than in ESSCs, suggesting that the signals of positive selection in ESSC genomes are an inheritance from normal tissue evolution, and more provocatively that the mutations might inhibit carcinogenesis16,17.