The mutational burden of aging As people age, they accumulate somatic mutations in healthy cells. About 25% of cells in normal, sun-exposed skin harbor cancer driver mutations. What about tissues not exposed to powerful mutagens like ultraviolet light? Martincorena et al. performed targeted gene sequencing of normal esophageal epithelium from nine human donors of varying age (see the Perspective by Chanock). The mutation rate was lower in esophagus than in skin, but there was a strong positive selection of clones carrying mutations in 14 cancer-associated genes. By middle age, more than half of the esophageal epithelium was colonized by mutant clones. Interestingly, mutations in the cancer driver gene NOTCH1 were more common in normal esophageal epithelium than in esophageal cancer. Science, this issue p. 911; see also p. 893 Cancer-associated mutations are surprisingly common in normal esophageal epithelium from human donors. 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 NOTCH1 and TP53 mutations affecting 12 to 80% and 2 to 37% of cells, respectively. Unexpectedly, the prevalence of NOTCH1 mutations in normal esophagus was several times higher than in esophageal cancers. These findings have implications for our understanding of cancer and aging.

中文翻译：

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随着年龄的增长，体细胞突变克隆在人类食道中定殖


衰老的突变负担随着人们年龄的增长，他们在健康细胞中积累体细胞突变。暴露在阳光下的正常皮肤中大约 25% 的细胞含有癌症驱动突变。未暴露于紫外线等强力诱变剂的组织又如何呢？马丁科雷纳等人。对来自九个不同年龄的人类捐赠者的正常食管上皮进行了靶向基因测序（参见 Chanock 的观点）。食道中的突变率低于皮肤中的突变率，但携带 14 个癌症相关基因突变的克隆具有很强的阳性选择。到了中年，超过一半的食管上皮被突变克隆定殖。有趣的是，癌症驱动基因 NOTCH1 的突变在正常食管上皮中比在食管癌中更常见。科学，本期第 14 页。 911；另见 p. 893 令人惊奇的是，癌症相关突变在人类捐赠者的正常食管上皮中非常常见。正常组织中的细胞在一生中积累突变的程度尚不清楚。一些突变细胞扩展成可以通过基因组测序检测到的克隆。我们在来自 9 名捐赠者（年龄范围为 20 至 75 岁）的正常食管上皮中绘制了突变克隆图谱。体细胞突变随着年龄的增长而积累，主要是由内在突变过程引起的。我们发现携带 14 个癌症基因突变的克隆具有强阳性选择，每平方厘米有数十到数百个克隆。在中年和老年捐赠者中，带有癌症相关突变的克隆覆盖了大部分上皮，NOTCH1 和 TP53 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NOTCH1突变的发生率比食管癌高出数倍。 这些发现对我们对癌症和衰老的理解具有重要意义。