The mutational landscape of normal human endometrial epithelium.

Autor: Moore L; Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK.; Department of Pathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK., Leongamornlert D; Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK., Coorens THH; Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK., Sanders MA; Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK.; Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands., Ellis P; Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK.; Inivata Ltd, Cambridge, UK., Dentro SC; Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK.; European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Cambridge, UK., Dawson KJ; Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK., Butler T; Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK., Rahbari R; Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK., Mitchell TJ; Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK., Maura F; 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 J; Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK., Tarpey PS; Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK., Brunner SF; Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK., Lee-Six H; Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK., Hooks Y; Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK., Moody S; Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK., Mahbubani KT; 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 M; Department of Pathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK., Brosens JJ; Tommy's National Miscarriage Research Centre, Warwick Medical School, University of Warwick, Coventry, UK., Iacobuzio-Donahue CA; 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 I; Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK., Saeb-Parsy K; Department of Surgery, University of Cambridge, Cambridge, UK.; Cambridge NIHR Biomedical Research Centre, Cambridge, UK., Campbell PJ; Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK., Stratton MR; Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Cambridge, UK. mrs@sanger.ac.uk.
Jazyk: angličtina
Zdroj: Nature [Nature] 2020 Apr; Vol. 580 (7805), pp. 640-646. Date of Electronic Publication: 2020 Apr 22.
DOI: 10.1038/s41586-020-2214-z
Abstrakt: 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.
Databáze: MEDLINE
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