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Cited by 96Endometriosis Research and TreatmentPlant and fungal interactionsEndometrial and Cervical Cancer Treatments

The DOI matches its Crossref record; 280 of the 280 references it cites were found in a registry or an index.

Cancer-associated mutations in endometriosis: shedding light on the pathogenesis and pathophysiology

Guo, Sun-Wei·2020·Human Reproduction Update
DOI 10.1093/humupd/dmz047
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Abstract

BACKGROUND: Endometriosis is a benign gynaecological disease. Thus, it came as a complete surprise when it was reported recently that the majority of deep endometriosis lesions harbour somatic mutations and a sizeable portion of them contain known cancer-associated mutations (CAMs). Four more studies have since been published, all demonstrating the existence of CAMs in different subtypes of endometriosis. While the field is still evolving, the confirmation of CAMs has raised many questions that were previously overlooked. OBJECTIVE AND RATIONALE: A comprehensive overview of CAMs in endometriosis has been produced. In addition, with the recently emerged understanding of the natural history of endometriotic lesions as well as CAMs in normal and apparently healthy tissues, this review attempts to address the following questions: Why has there been such a wild discrepancy in reported mutation frequencies? Why does ectopic endometrium have a higher mutation rate than that of eutopic endometrium? Would the presence of CAMs in endometriotic lesions increase the risk of cancer to the bearers? Why do endometriotic epithelial cells have much higher mutation frequencies than their stromal counterpart? What clinical implications, if any, do the CAMs have for the bearers? Do these CAMs tell us anything about the pathogenesis and/or pathophysiology of endometriosis? SEARCH METHODS: The PubMed database was searched, from its inception to September 2019, for all papers in English using the term ‘endometriosis and CAM’, ‘endometriosis and cancer-driver mutation’, ‘somatic mutations’, ‘fibrosis’, ‘fibrosis and epigenetic’, ‘CAMs and tumorigenesis’, ‘somatic mutation and normal tissues’, ‘oestrogen receptor and fibrosis’, ‘oxidative stress and fibrosis’, ‘ARID1A mutation’, and ‘Kirsten rat sarcoma mutation and therapeutics’. All retrieved papers were read and, when relevant, incorporated into the review results. OUTCOMES: Seven papers that identified CAMs in endometriosis using various sequencing methods were retrieved, and their results were somewhat different. Yet, it is apparent that those using microdissection techniques and more accurate sequencing methods found more CAMs, echoing recent discoveries that apparently healthy tissues also harbour CAMs as a result of the replicative aging process. Hence endometriotic lesions, irrespective of subtype, if left intact, would generate CAMs as part of replicative aging, oxidative stress and perhaps other factors yet to be identified and, in some rare cases, develop cancer. The published data still are unable to paint a clear picture on pathogenesis of endometriosis. However, since endometriotic epithelial cells have a higher turnover than their stromal counterpart due to cyclic bleeding, and since the endometriotic stromal component can be formed by refresh influx of mesenchymal cells through epithelial–mesenchymal transition, endothelial–mesenchymal transition, mesothelial–mesenchymal transition and other processes as well as recruitment of bone-marrow-derived stem cells and outflow due to smooth muscle metaplasia, endometriotic epithelial cells have much higher mutation frequencies than their stromal counterpart. The epithelial and stromal cellular components develop in a dependent and co-evolving manner. Genes involved in CAMs are likely to be active players in lesional fibrogenesis, and hyperestrogenism and oxidative stress are likely drivers of both CAMs and fibrogenesis. Finally, endometriotic lesions harbouring CAMs would conceivably be more refractory to medical treatment, due, in no small part, to their high fibrotic content and reduced vascularity and cellularity. WIDER IMPLICATIONS: The accumulating data on CAMs in endometriosis have shed new light on the pathogenesis and pathophysiology of endometriosis. They also suggest new challenges in management. The distinct yet co-evolving developmental trajectories of endometriotic stroma and epithelium underscore the importance of the lesional microenvironment and ever-changing cellular identity. Mutational profiling of normal endometrium from women of different ages and reproductive history is needed in order to gain a deeper understanding of the pathogenesis. Moreover, one area that has conspicuously received scant attention is the epigenetic landscape of ectopic, eutopic and normal endometrium.

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Metadata

Authors
Guo, S.-W.
Affiliations
Fudan University (CN)
Corresponding author
Guo, Sun-Wei
ORCID
Guo, Sun-Wei
Venue
Human Reproduction Update
Publisher
Oxford University Press (OUP)
Published
2020-03-10
Volume
26
Issue
3
Pages
423-449
ISSN
  • 1355-4786 (ISSN-L)
  • 1460-2369
DOI
10.1093/humupd/dmz047
OpenAlex
W3011721387
Cited by
96
References
280
Citations by year
2026: 15 · 2025: 15 · 2024: 8 · 2023: 15 · 2022: 20 · 2021: 13 · 2020: 10
FWCI
1.51
Type
journal article
Language
en
Open access
closed
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • Human Reproduction Update (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Science Foundation of China (81771553, 81530040)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
  • Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Plant and fungal interactions
  • Health Sciences › Medicine › Obstetrics and Gynecology › Endometrial and Cervical Cancer Treatments
Keywords
endometriosis, cancer-associated mutations, somatic mutations, deep infiltrating endometriosis, endometriotic lesions, endometriosis pathogenesis, endometriosis pathophysiology, ectopic endometrium, eutopic endometrium, replicative senescence, oxidative stress, fibrosis, epigenetics, oestrogen receptor, ARID1A mutation, KRAS mutation, carcinogenesis
MeSH terms
Bone Marrow Cells, Endometriosis, Endometrium, Epithelial Cells, Female, Humans, Mutation, Neoplasms, Ovarian Diseases, Epithelial-Mesenchymal Transition, Tumor Microenvironment

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