The mutational landscape of normal human endometrial epithelium
The mutational landscape of normal human endometrial epithelium
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DOI：
10.1038/s41586-020-2214-z
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发表时间：
2020-04-22
期刊：
影响因子：
64.8
通讯作者：
Stratton, Michael R.
中科院分区：
文献类型：
--
作者：
Moore, Luiza;Leongamornlert, Daniel;Stratton, Michael R.
所有正常的体细胞都被认为获得了突变，但对正常细胞的体细胞突变的比率、模式、原因和后果的了解有限。子宫内膜在一生中处于多种生理状态，并由腺体形成的上皮(1，2)衬里。在这里，使用全基因组测序，我们表明，正常人类子宫内膜腺是克隆细胞群体，总突变负荷每年增加约29个碱基替换，比子宫内膜癌的突变负荷低许多倍。正常的子宫内膜腺经常携带癌症基因的“驱动”突变，这种突变的负担随着年龄的增长而增加，随着产次的增加而减少。带有驱动因素的细胞克隆通常起源于生命的最初几十年，随后逐渐定植于子宫内膜的上皮衬里。我们的结果显示，正常组织之间的突变情况明显不同--可能是由于它们的结构和生理上的差异--表明导致子宫内膜癌的肿瘤性变化的过程是在生命早期开始的。对正常人类子宫内膜腺的全基因组测序显示，大多数是克隆细胞群体，经常携带早期发生的癌症驱动基因突变，产次具有保护作用。
All normal somatic cells are thought to acquire mutations, but understanding of the rates, patterns, causes and consequences of somatic mutations in normal cells is limited. The uterine endometrium adopts multiple physiological states over a lifetime and is lined by a gland-forming epithelium(1,2). Here, using whole-genome sequencing, we show that normal human endometrial glands are clonal cell populations with total mutation burdens that increase at about 29 base substitutions per year and that are many-fold lower than those of endometrial cancers. Normal endometrial glands frequently carry 'driver' mutations in cancer genes, the burden of which increases with age and decreases with parity. Cell clones with drivers often originate during the first decades of life and subsequently progressively colonize the epithelial lining of the endometrium. Our results show that mutational landscapes differ markedly between normal tissues-perhaps shaped by differences in their structure and physiology-and indicate that the procession of neoplastic change that leads to endometrial cancer is initiated early in life.Whole-genome sequencing of normal human endometrial glands shows that most are clonal cell populations and frequently carry cancer driver mutations that occur early in life, and that parity has a protective effect.