Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
Department of Clinical Oncology, Kyoto University Hospital, Kyoto, Japan.
Nature. 2019 Jan;565(7739):312-317. doi: 10.1038/s41586-018-0811-x. Epub 2019 Jan 2.
Clonal expansion in aged normal tissues has been implicated in the development of cancer. However, the chronology and risk dependence of the expansion are poorly understood. Here we intensively sequence 682 micro-scale oesophageal samples and show, in physiologically normal oesophageal epithelia, the progressive age-related expansion of clones that carry mutations in driver genes (predominantly NOTCH1), which is substantially accelerated by alcohol consumption and by smoking. Driver-mutated clones emerge multifocally from early childhood and increase their number and size with ageing, and ultimately replace almost the entire oesophageal epithelium in the extremely elderly. Compared with mutations in oesophageal cancer, there is a marked overrepresentation of NOTCH1 and PPM1D mutations in physiologically normal oesophageal epithelia; these mutations can be acquired before late adolescence (as early as early infancy) and significantly increase in number with heavy smoking and drinking. The remodelling of the oesophageal epithelium by driver-mutated clones is an inevitable consequence of normal ageing, which-depending on lifestyle risks-may affect cancer development.
克隆扩增在衰老的正常组织中与癌症的发展有关。然而，这种扩增的时间顺序和风险依赖性还知之甚少。在这里，我们对 682 个微尺度食管样本进行了深入测序，并在生理正常的食管上皮中显示，携带驱动基因（主要是 NOTCH1）突变的克隆随着年龄的增长而逐渐扩增，而饮酒和吸烟则大大加速了这种扩增。驱动突变的克隆在儿童早期就呈多灶性出现，并随着年龄的增长增加其数量和大小，最终在非常年长的人群中取代几乎整个食管上皮。与食管癌中的突变相比，生理正常的食管上皮中 NOTCH1 和 PPM1D 突变明显过表达；这些突变可以在青春期前（早在婴儿期）获得，并随着大量吸烟和饮酒而显著增加。驱动突变克隆对食管上皮的重塑是正常衰老的必然结果，这种重塑——取决于生活方式的风险——可能会影响癌症的发展。
