Human epithelial tissues accumulate cancer-driver mutations with age^{1,2,3,4,5,6,7,8,9}, yet tumour formation remains rare. The positive selection of these mutations suggests that they alter the behaviour and fitness of proliferating cells^10,11,12. Thus, normal adult tissues become a patchwork of mutant clones competing for space and survival, with the fittest clones expanding by eliminating their less competitive neighbours^11,12,13,14. However, little is known about how such dynamic competition in normal epithelia influences early tumorigenesis. Here we show that the majority of newly formed oesophageal tumours are eliminated through competition with mutant clones in the adjacent normal epithelium. We followed the fate of nascent, microscopic, pre-malignant tumours in a mouse model of oesophageal carcinogenesis and found that most were rapidly lost with no indication of tumour cell death, decreased proliferation or an anti-tumour immune response. However, deep sequencing of ten-day-old and one-year-old tumours showed evidence of selection on the surviving neoplasms. Induction of highly competitive clones in transgenic mice increased early tumour removal, whereas pharmacological inhibition of clonal competition reduced tumour loss. These results support a model in which survival of early neoplasms depends on their competitive fitness relative to that of mutant clones in the surrounding normal tissue. Mutant clones in normal epithelium have an unexpected anti-tumorigenic role in purging early tumours through cell competition, thereby preserving tissue integrity.

人类上皮组织在^{1、2、3、4、5、6、7、8、9}岁时积累癌症驱动突变，但肿瘤形成仍然很少见。这些突变的阳性选择表明它们改变了增殖细胞的行为和适应性^10,11,12 。因此，正常的成体组织变成了竞争空间和生存的突变克隆的拼凑而成，最适应的克隆通过消除竞争性较弱的邻居来扩展^11,12,13,14 。然而，人们对正常上皮细胞中的这种动态竞争如何影响早期肿瘤发生知之甚少。在这里，我们表明，大多数新形成的食管肿瘤通过与邻近正常上皮中的突变克隆竞争而被消除。我们追踪了食管癌小鼠模型中新生的、微观的、癌前肿瘤的命运，发现大多数肿瘤迅速消失，没有任何迹象显示肿瘤细胞死亡、增殖减少或抗肿瘤免疫反应。然而，对十天和一年的肿瘤进行深度测序显示了对存活肿瘤的选择证据。在转基因小鼠中诱导高度竞争性的克隆可以增加早期肿瘤的去除，而克隆竞争的药理学抑制则可以减少肿瘤的损失。这些结果支持了一个模型，其中早期肿瘤的存活取决于它们相对于周围正常组织中突变克隆的竞争适应性。正常上皮中的突变克隆在通过细胞竞争清除早期肿瘤方面具有意想不到的抗肿瘤作用，从而保持组织完整性。