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The mutational landscape of normal human endometrial epithelium

机译：正常人子宫内膜上皮的突变情况

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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.
机译：人们认为所有正常的体细胞都具有突变，但是对正常细胞中体细胞突变的发生率，模式，原因和后果的了解是有限的。子宫内膜在一生中具有多种生理状态，并由形成腺体的上皮（1,2）排列。在这里，使用全基因组测序，我们显示正常人子宫内膜腺体是克隆细胞群，其总突变负担每年以约29个碱基取代增加，并且比子宫内膜癌低很多倍。正常子宫内膜腺体经常在癌症基因中携带“驱动”突变，其负担随着年龄的增长而增加，而随着胎次的减少而减少。具有驱动因子的细胞克隆通常起源于生命的最初几十年，然后逐渐在子宫内膜的上皮内层定植。我们的研究结果表明，正常组织之间的突变格局存在显着差异-可能是由于其结构和生理差异而形成的-并表明导致子宫内膜癌的肿瘤改变过程在生命的早期就开始了。正常人子宫内膜腺的全基因组测序研究表明，大多数是克隆细胞群，并经常携带生命早期发生的癌症驱动基因突变，并且奇偶校验具有保护作用。

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    《Nature》 |2020年第7805期|640-646|共7页
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    Wellcome Sanger Inst CASM Cambridge England|Cambridge Univ Hosp NHS Fdn Trust Dept Pathol Cambridge England;

    Wellcome Sanger Inst CASM Cambridge England;

    Wellcome Sanger Inst CASM Cambridge England|Erasmus MC Dept Hematol Rotterdam Netherlands;

    Wellcome Sanger Inst CASM Cambridge England|Inivata Ltd Cambridge England;

    Wellcome Sanger Inst CASM Cambridge England|European Bioinformat Inst EMBL EBI European Mol Biol Lab Cambridge England;

    Wellcome Sanger Inst CASM Cambridge England|Mem Sloan Kettering Canc Ctr Dept Med Myeloma Serv 1275 York Ave New York NY 10021 USA;

    Univ Cambridge Dept Surg Cambridge England|Cambridge NIHR Biomed Res Ctr Cambridge England|Univ Cambridge Dept Haematol Cambridge England;

    Cambridge Univ Hosp NHS Fdn Trust Dept Pathol Cambridge England;

    Univ Warwick Warwick Med Sch Tommys Natl Miscarriage Res Ctr Coventry W Midlands England;

    Mem Sloan Kettering Canc Ctr Dept Pathol 1275 York Ave New York NY 10021 USA|Mem Sloan Kettering Canc Ctr Human Oncol & Pathogenesis Program 1275 York Ave New York NY 10021 USA;

    Univ Cambridge Dept Surg Cambridge England|Cambridge NIHR Biomed Res Ctr Cambridge England;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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