Notch1mutation drives clonal expansion in normal esophageal epithelium but impairs tumor growth

SummaryNOTCH1mutant clones occupy the majority of normal human esophagus by middle age, but are comparatively rare in esophageal cancers, suggestingNOTCH1mutations may promote clonal expansion but impede carcinogenesis1–3. Here we test this hypothesis. Visualizing and sequencingNOTCH1mutant clones in aging normal human esophagus reveals frequent biallelic mutations that block NOTCH1 signaling. In mouse esophagus, heterozygousNotch1mutation confers a competitive advantage over wild type cells, an effect enhanced by loss of the second allele.Notch1loss alters transcription but has minimal effects on epithelial structure and cell dynamics. In a carcinogenesis model,Notch1mutations were less prevalent in tumors than normal epithelium. Deletion ofNotch1reduced tumor growth, an effect recapitulated by anti-NOTCH1 antibody treatment. We conclude thatNotch1mutations in normal epithelium are beneficial as wild typeNotch1promotes tumor expansion. NOTCH1 blockade may have therapeutic potential in preventing esophageal squamous cancer.