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PMID: 32350471 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

The mutational landscape of normal human endometrial epithelium.

Nature ·Vol. 580 ·No. 7805 ·2020-00-00 ·Pages 640-646

Moore L, Leongamornlert D, Coorens THH, Sanders MA, Ellis P, Dentro SC, Dawson KJ, Butler T, Rahbari R, Mitchell TJ, Maura F, Nangalia J, Tarpey PS, Brunner SF, Lee-Six H, Hooks Y, Moody S, Mahbubani KT, Jimenez-Linan M, Brosens JJ, Iacobuzio-Donahue CA, Martincorena I, Saeb-Parsy K, Campbell PJ, Stratton MR

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.

MeSH Terms
Adult Age of Onset Aged Aged, 80 and over Aging/genetics Carcinogenesis/genetics Clone Cells/cytology DNA Mutational Analysis Endometrial Neoplasms/genetics Endometrium/cytology,metabolism,pathology Epithelial Cells/cytology,metabolism,pathology Epithelium/metabolism,pathology Female Health Humans Middle Aged Mutation Parity/genetics Time Factors Young Adult
Authors & Affiliations
25 authors, click to expand affiliations / ORCID
Moore Luiza ORCID
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK. | Department of Pathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Leongamornlert Daniel
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK.
Coorens Tim H H
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK.
Sanders Mathijs A
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK. | Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Ellis Peter
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK. | Inivata Ltd, Cambridge, UK.
Dentro Stefan C
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK. | European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Cambridge, UK.
Dawson Kevin J
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK.
Butler Tim ORCID
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK.
Rahbari Raheleh ORCID
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK.
Mitchell Thomas J ORCID
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK.
Maura Francesco
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK. | Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nangalia Jyoti
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK.
Tarpey Patrick S
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK.
Brunner Simon F
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK.
Lee-Six Henry ORCID
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK.
Hooks Yvette
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK.
Moody Sarah
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK.
Mahbubani Krishnaa T ORCID
Department of Surgery, University of Cambridge, Cambridge, UK. | Cambridge NIHR Biomedical Research Centre, Cambridge, UK. | Department of Haematology, University of Cambridge, Cambridge, UK.
Jimenez-Linan Mercedes
Department of Pathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Brosens Jan J ORCID
Tommy's National Miscarriage Research Centre, Warwick Medical School, University of Warwick, Coventry, UK.
Iacobuzio-Donahue Christine A ORCID
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. | Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Martincorena Inigo
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK.
Saeb-Parsy Kourosh ORCID
Department of Surgery, University of Cambridge, Cambridge, UK. | Cambridge NIHR Biomedical Research Centre, Cambridge, UK.
Campbell Peter J ORCID
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK.
Stratton Michael R ORCID
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK. [email protected].
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/s41586-020-2214-z
Email
[email protected]
Published
2020-00-00
Epub
2020-00-22
Pages
640-646
Language
English
Region
England
NLM ID
0410462
Subset
IM
Corrections
CommentIn
PMID: 32322030
External Links
PubMed source DOI: 10.1038/s41586-020-2214-z View journal details
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