The mutational landscape of normal human endometrial epithelium

被引：338

作者：

Moore, Luiza ^{[1
,2
]}

Leongamornlert, Daniel ^{[1
]}

Coorens, Tim H. H. ^{[1
]}

Sanders, Mathijs A. ^{[1
,3
]}

Ellis, Peter ^{[1
,4
]}

Dentro, Stefan C. ^{[1
,5
]}

Dawson, Kevin J. ^{[1
]}

Butler, Tim ^{[1
]}

Rahbari, Raheleh ^{[1
]}

Mitchell, Thomas J. ^{[1
]}

Maura, Francesco ^{[1
,6
]}

Nangalia, Jyoti ^{[1
]}

Tarpey, Patrick S. ^{[1
]}

Brunner, Simon F. ^{[1
]}

Lee-Six, Henry ^{[1
]}

Hooks, Yvette ^{[1
]}

Moody, Sarah ^{[1
]}

Mahbubani, Krishnaa T. ^{[7
,8
,9
]}

Jimenez-Linan, Mercedes ^{[2
]}

Brosens, Jan J. ^{[10
]}

Iacobuzio-Donahue, Christine A. ^{[11
,12
]}

Martincorena, Inigo ^{[1
]}

Saeb-Parsy, Kourosh ^{[7
,8
]}

Campbell, Peter J. ^{[1
]}

Stratton, Michael R. ^{[1
]}

机构：

[1] Wellcome Sanger Inst, CASM, Cambridge, England

[2] Cambridge Univ Hosp NHS Fdn Trust, Dept Pathol, Cambridge, England

[3] Erasmus MC, Dept Hematol, Rotterdam, Netherlands

[4] Inivata Ltd, Cambridge, England

[5] European Bioinformat Inst EMBL EBI, European Mol Biol Lab, Cambridge, England

[6] Mem Sloan Kettering Canc Ctr, Dept Med, Myeloma Serv, 1275 York Ave, New York, NY 10021 USA

[7] Univ Cambridge, Dept Surg, Cambridge, England

[8] Cambridge NIHR Biomed Res Ctr, Cambridge, England

[9] Univ Cambridge, Dept Haematol, Cambridge, England

[10] Univ Warwick, Warwick Med Sch, Tommys Natl Miscarriage Res Ctr, Coventry, W Midlands, England

[11] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA

[12] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA

来源：

NATURE | 2020年 / 580卷 / 7805期

基金：

瑞士国家科学基金会; 英国惠康基金;

关键词：

CANCER-ASSOCIATED MUTATIONS; SOMATIC MUTATIONS; STEM-CELLS; CLONAL HEMATOPOIESIS; RISK; DIVERSIFICATION; EXPANSION; SELECTION; PATTERN;

D O I：

10.1038/s41586-020-2214-z

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：640 / +

页数：24

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