Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
MRC Cancer Unit, Hutchison-MRC Research Centre, University of Cambridge, Cambridge CB2 0XZ, UK.
Science. 2018 Nov 23;362(6417):911-917. doi: 10.1126/science.aau3879. Epub 2018 Oct 18.
The extent to which cells in normal tissues accumulate mutations throughout life is poorly understood. Some mutant cells expand into clones that can be detected by genome sequencing. We mapped mutant clones in normal esophageal epithelium from nine donors (age range, 20 to 75 years). Somatic mutations accumulated with age and were caused mainly by intrinsic mutational processes. We found strong positive selection of clones carrying mutations in 14 cancer genes, with tens to hundreds of clones per square centimeter. In middle-aged and elderly donors, clones with cancer-associated mutations covered much of the epithelium, with and mutations affecting 12 to 80% and 2 to 37% of cells, respectively. Unexpectedly, the prevalence of mutations in normal esophagus was several times higher than in esophageal cancers. These findings have implications for our understanding of cancer and aging.
正常组织中的细胞在一生中积累突变的程度尚不清楚。一些突变细胞会扩增成克隆，这些克隆可以通过基因组测序检测到。我们对来自 9 位供体（年龄范围为 20 至 75 岁）的正常食管上皮中的突变克隆进行了定位。体细胞突变随年龄增长而积累，主要是由内在的突变过程引起的。我们发现携带 14 个癌症基因突变的克隆受到强烈的正选择，每平方厘米有数十到数百个克隆。在中年和老年供体中，带有癌症相关突变的克隆覆盖了大部分上皮组织， 和 突变分别影响 12%至 80%和 2%至 37%的细胞。出乎意料的是，正常食管中 突变的发生率比食管癌高几倍。这些发现对我们理解癌症和衰老具有重要意义。
