NOTCH1 基因突变克隆在中年时占据了大部分正常人食道，但在食道癌中相对较少，这表明 NOTCH1 突变促进了克隆扩张但阻碍了癌变的发生。在这里，我们测试了这个假设。在人类衰老的食道中测序 NOTCH1 突变克隆，发现常见的双等位基因突变可以阻断 NOTCH1 信号通路。在小鼠食道中，杂合 Notch1 基因突变与野生型细胞相比，具有竞争优势，这种效应在第二等位基因缺失时得到加强。广泛的 Notch1 丧失改变了转录，但对上皮结构和细胞动力学的影响很小。在癌变模型中，Notch1 基因突变在肿瘤中不如正常上皮细胞普遍。删除 Notch1 基因可以减缓肿瘤生长，而抗-NOTCH1 抗体治疗也可以重现这种效应。 Notch1 基因的丧失可导致肿瘤细胞增殖减少。我们得出结论，正常上皮细胞中的 Notch1 基因突变有益，因为野生型 Notch1 有利于肿瘤扩张。NOTCH1 阻断可能具有预防食道鳞状癌的治疗潜力。© 2023。作者（们）。

NOTCH1 mutant clones occupy the majority of normal human esophagus by middle age but are comparatively rare in esophageal cancers, suggesting NOTCH1 mutations drive clonal expansion but impede carcinogenesis. Here we test this hypothesis. Sequencing NOTCH1 mutant clones in aging human esophagus reveals frequent biallelic mutations that block NOTCH1 signaling. In mouse esophagus, heterozygous Notch1 mutation confers a competitive advantage over wild-type cells, an effect enhanced by loss of the second allele. Widespread Notch1 loss alters transcription but has minimal effects on the epithelial structure and cell dynamics. In a carcinogenesis model, Notch1 mutations were less prevalent in tumors than normal epithelium. Deletion of Notch1 reduced tumor growth, an effect recapitulated by anti-NOTCH1 antibody treatment. Notch1 null tumors showed reduced proliferation. We conclude that Notch1 mutations in normal epithelium are beneficial as wild-type Notch1 favors tumor expansion. NOTCH1 blockade may have therapeutic potential in preventing esophageal squamous cancer.© 2023. The Author(s).