Somatic mutant clones colonize the human esophagus with age.

Somatic mutant clones colonize the human esophagus with age.
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DOI:
10.1126/science.aau3879
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发表时间:
2018-11-23
期刊:
Science (New York, N.Y.)
影响因子:
--
通讯作者:
Jones PH
Jones PH
中科院分区:
其他
文献类型:
--
作者:
Martincorena I;Fowler JC;Wabik A;Lawson ARJ;Abascal F;Hall MWJ;Cagan A;Murai K;Mahbubani K;Stratton MR;Fitzgerald RC;Handford PA;Campbell PJ;Saeb-Parsy K;Jones PH

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人们对正常组织中的细胞在一生中积累突变的程度知之甚少。一些突变细胞扩展成可以通过基因组测序检测的克隆。我们映射突变克隆正常食管上皮9个捐助者(年龄范围20至75岁)。体细胞突变随着年龄的增长而积累,主要由内在突变过程引起。我们发现了携带14个癌症基因突变的克隆的强阳性选择,每平方厘米有数十到数百个克隆。在中年和老年供体中,具有癌症相关突变的克隆覆盖了大部分上皮细胞,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,NOTCH1突变在正常食管中的患病率是食管癌的数倍。这些发现对我们理解癌症和衰老具有重要意义。
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 mainly caused 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 ageing.
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