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The mutational landscape of normal human endometrial epithelium
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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. 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.
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“Taken together, these results demonstrate the significant advantage the toolkit we have developed in this study has to generate isogenic models of novel mutations in early tumorigenesis48,50–52.”
From One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids (2023) · cites this paper as [51]
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“While this hypothesis has been previously proposed48,50–52, it had never before been tested in an isogenic model.”
From One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids (2023) · cites this paper as [51]
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BackgroundReconstructing phylogenetic trees from genome-wide somatic mutations in clonal samples
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“Recent exome sequencing and whole-genome sequencing studies revealed that MLL3/4 and UTX mutations are not only found in tumor tissues but are also present in normal tissues such as esophagus (41, 42), endometrial epithelium (43), urothelium (27, 32), skin, and lung (44).”
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ResultMutational selection in normal urothelium
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BackgroundLineage tracing in human tissues
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MethodAn expanded view of cell competition
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PP2A and E3 ubiquitin ligase deficiencies: Seminal biological drivers in endometrial cancer
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“The missense mutation G12V contributes to HRAS oncogenicity by stabilizing this protein in a constitutively active GTP-bound state [3,4].”
BackgroundThe long road of drug development for endometriosis – Pains, gains, and hopes
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BackgroundThe human placenta exhibits a unique transcriptomic void
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“Instead, the pattern seems more consistent with a model where clone sizes are constrained (by cell-intrinsic or cell-extrinsic mechanisms) (see Supplementary Notes 5,6, Extended Data Fig.”
BackgroundSelf-citationIs endometriosis due to evolutionary maladaptation?
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Self-citationReflected stemness as a potential driver of the tumour microenvironment
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Telomere Crisis Shapes Cancer EvolutionPreprint
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“Nonetheless, a uterine origin provides a simple and attractive source for the cell types involved, and somatic genetic data may favour this aetiology (Anglesio et al. , 2017; Suda et al. , 2018; Lac et al. , 2019a; Moore et al. , 2020; Praetorius et al. , 2022; Yamaguchi et al. , 2022).”
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“60 Our current study reinforces the importance of shutting-down both pathways, because sensitivity to GC, an essential component of ALL therapy, primarily depends on mTORC1-mediated signals in B-ALL cells.”
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“Recent studies have shown that some cancer associated recurrent mutations are also identi fi ed in normal cells from the same epithelium 23,24 , proposing that tissue-speci fi c transformation likely requires additional factors such as environmental exposures, additional mutations or ineffective…”
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Mutations observed in somatic evolution reveal underlying gene mechanisms
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“3b and Supplementary Note 4).”
A cellular and molecular portrait of endometriosis subtypesPreprint
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Metadata
- Authors
- Moore, L., Leongamornlert, D., Coorens, T. H. H., Sanders, M. A., Ellis, P., Dentro, S. C., Dawson, K. J., Butler, T., Rahbari, R., Mitchell, T. J., Maura, F., Nangalia, J., Tarpey, P. S., Brunner, S. F., Lee-Six, H., Hooks, Y., Moody, S., Mahbubani, K. T., Jimenez-Linan, M., Brosens, J. J., Iacobuzio-Donahue, C. A., Martincorena, I., Saeb-Parsy, K., Campbell, P. J., & Stratton, M. R.
- Affiliations
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Wellcome Sanger Institute (GB)
- Erasmus MC (NL)
- European Bioinformatics Institute (GB)
- Memorial Sloan Kettering Cancer Center (US)
- University of Cambridge (GB)
- University of Warwick (GB)
- Corresponding author
- Stratton, Michael R.
- ORCID
- Moore, Luiza
- Leongamornlert, Daniel
- Coorens, Tim H. H.
- Sanders, Mathijs A.
- Dentro, Stefan C.
- Butler, Tim
- Rahbari, Raheleh
- Mitchell, Thomas J.
- Maura, Francesco
- Nangalia, Jyoti
- Tarpey, Patrick S.
- Lee-Six, Henry
- Moody, Sarah
- Mahbubani, Krishnaa T.
- Brosens, Jan J.
- Iacobuzio-Donahue, Christine A.
- Saeb-Parsy, Kourosh
- Campbell, Peter J.
- Stratton, Michael R.
- Venue
- Nature
- Published
- 2020-04-22
- Volume
- 580
- Issue
- 7805
- Pages
- 640-646
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W3020114628
- Semantic Scholar
- 64bced314a97056c50b400d859c78993c4ce2fd8
- Cited by
- 499
- References
- 64
- Citations by year
- 2026: 42 · 2025: 54 · 2024: 69 · 2023: 87 · 2022: 91 · 2021: 89 · 2020: 51
- FWCI
- 27.19
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Science Foundation
- European Hematology Association (TRTH182)
- Wellcome Trust (103858/Z/14/Z)
- Cancer Research UK (C20/A20917, 23917, 27176, 21777, 27114)
- Pathological Society of Great Britain and Ireland
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (171753, 180790)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (019.153LW.038)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Epidemiology › Cervical Cancer and HPV Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- somatic mutations, endometrial epithelium, endometrial cancer, clonal cell populations, mutational burden, driver mutations, cancer genes, parity, aging, mutational landscape, tumor progression, endometrial glands
- MeSH terms
- Adult, Aged, Aged, 80 and over, Aging, Clone Cells, DNA Mutational Analysis, Endometrium, Epithelial Cells, Epithelium, Female, Health, Humans, Middle Aged, Mutation, Parity, Time Factors, Endometrial Neoplasms, Age of Onset, Young Adult, Carcinogenesis
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