The mutational landscape of normal human endometrial epithelium

Luiza Moore, Daniel Leongamornlert, Tim H. H. Coorens, Mathijs A. Sanders, Peter Ellis, Stefan C. Dentro, Kevin J. Dawson, Tim Butler, Raheleh Rahbari, Thomas J. Mitchell, Francesco Maura, Jyoti Nangalia, Patrick S. Tarpey, Simon F. Brunner, Henry Lee-Six, Yvette Hooks, Sarah Moody, Krishnaa T. Mahbubani, Mercedes Jimenez-Linan, Jan J. Brosens, Christine A. Iacobuzio-Donahue, Inigo Martincorena, Kourosh Saeb-Parsy, Peter J. Campbell and Michael R. Stratton ()
Additional contact information
Luiza Moore: Wellcome Sanger Institute
Daniel Leongamornlert: Wellcome Sanger Institute
Tim H. H. Coorens: Wellcome Sanger Institute
Mathijs A. Sanders: Wellcome Sanger Institute
Peter Ellis: Wellcome Sanger Institute
Stefan C. Dentro: Wellcome Sanger Institute
Kevin J. Dawson: Wellcome Sanger Institute
Tim Butler: Wellcome Sanger Institute
Raheleh Rahbari: Wellcome Sanger Institute
Thomas J. Mitchell: Wellcome Sanger Institute
Francesco Maura: Wellcome Sanger Institute
Jyoti Nangalia: Wellcome Sanger Institute
Patrick S. Tarpey: Wellcome Sanger Institute
Simon F. Brunner: Wellcome Sanger Institute
Henry Lee-Six: Wellcome Sanger Institute
Yvette Hooks: Wellcome Sanger Institute
Sarah Moody: Wellcome Sanger Institute
Krishnaa T. Mahbubani: University of Cambridge
Mercedes Jimenez-Linan: Cambridge University Hospitals NHS Foundation Trust
Jan J. Brosens: University of Warwick
Christine A. Iacobuzio-Donahue: Memorial Sloan Kettering Cancer Center
Inigo Martincorena: Wellcome Sanger Institute
Kourosh Saeb-Parsy: University of Cambridge
Peter J. Campbell: Wellcome Sanger Institute
Michael R. Stratton: Wellcome Sanger Institute

Nature, 2020, vol. 580, issue 7805, 640-646

Abstract: Abstract 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 epithelium1,2. 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.

Date: 2020
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DOI: 10.1038/s41586-020-2214-z

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