Endometriosis is a prevalent gynecological condition associated with pelvic pain and infertility. Despite more than a century of research, the etiology of endometriosis still eludes scientific consensus. This lack of clarity has resulted in suboptimal prevention, diagnosis, and treatment options. Evidence of genetic contributors to endometriosis is interesting but limited; however, significant progress has been made in recent years in identifying epigenetic role in the pathogenesis of endometriosis through clinical studies, in vitro cell culture experiments, and in vivo animal models. The predominant findings include endometriosis-related differential expression of DNA methyltransferases and demethylases, histone deacetylases, methyltransferases, and demethylases, and regulators of chromatin architecture. There is also an emerging role for miRNAs in the control of epigenetic regulators in the endometrium and endometriosis. Changes in these epigenetic regulators result in differential chromatin organization and DNA methylation with consequences for gene expression independent of a genetic sequence. Epigenetically altered expression of genes related to steroid hormone production and signaling, immune regulation, and endometrial cell identity and function have all been identified and appear to play into the pathophysiological mechanisms of endometriosis as well as resulting infertility. This review summarizes and critically discusses early seminal findings, the ever-growing recent evidence of epigenetic contributions to the pathophysiology of endometriosis, and implications for proposed epigenetically targeted therapeutics.

Epigenetic Dysregulation in Endometriosis: Implications for Pathophysiology and Therapeutics.

Research advances in endometriosis-related signaling pathways: A review.

Endometriosis is a chronic condition affecting reproductive-aged women, characterized by the growth of ectopic endometrial tissue. Despite being benign, endometriosis is associated with an increased risk of certain cancers, including endometriosis-associated ovarian cancer (EAOC). Ovarian cancer is rare, but more common in women with endometriosis, particularly endometrioid and clear-cell carcinomas. Factors such as hormonal imbalance, reproductive history, environmental exposures, and genetic predisposition contribute to the malignant transformation of endometriosis. Thus, understanding potential risk factors causing malignancy is crucial. Over the past few decades, various genetic mutations, microRNAs, as well as tumor microenvironmental factors have been identified, impacting pathways like PI3K/AKT/mTOR, DNA repair mechanisms, oxidative stress, and inflammation. Thus, this review aims to summarize molecular studies involved in EAOC pathogenesis as potential therapeutic targets. However, further research is needed to better understand the molecular and environmental factors driving EAOC development, to target the susceptibility of endometriotic lesions to malignant progression, and to identify effective therapeutic strategies.

Endometriosis-Associated Ovarian Cancer: From Molecular Pathologies to Clinical Relevance

Adequate surgical management of malignant endometriosis remains a clinical challenge in gynecology. Age, sonography variables, and tumor biomarkers have been reported as candidates in the clinical decision. This study aims were to analyze the factors of women’s age, body mass index, ultrasound features, and tumor biomarkers to predict endometriosis-associated ovarian cancer in a large series of endometriomas and to study the surgical treatment performed in this cohort. In this retrospective study, we reviewed the medical records of patients with ultrasound diagnosis of ovarian cyst classified as endometrioma (benign as well as with risk of malignancy), surgically treated in the endometriosis unit of Hospital Universitario La Paz (Madrid, Spain) between January 2019 and July 2021. According to the final histology examination, the women were clustered as non-endometriosis-associated ovarian cancer (OE, benign endometriomas, n = 59) and endometriosis-associated ovarian cancer (EAOC) (n = 17). Demographic, clinical, and surgical data were collected from these women. International Ovarian Tumor Analysis (IOTA) criteria were assessed for the ultrasound examination. The age of the women in the EAOC group was 50.0 [43.0; 63.0] years, which was significantly higher than OE (39.0 [34.0; 46.0] years; p-value < 0.001). In addition, the body mass index for the OE group (24.9 ± 5.3 kg/m2) was significantly higher than for the EAOC group (23.3 ± 4.6 kg/m2; p-value < 0.001). However, the tumor biomarker levels (CA 125, CA 19.9 and He4) were not significantly different among the groups. We performed 51.4% cystectomies and 48.6% adnexectomies, with an association between the adnexectomy and EAOC group (p-value < 0.001). In addition, a significant association was found between ultrasound features suspicious for malignancy and the EAOC group. Conclusively, women’s age and ultrasound features, such as papillary projections, septa, and positive echo-Doppler, were the main factors to consider when evaluating the malignancy risk associated with endometriosis.

/pdf/evaluation-of-womens-age-and-ultrasonographic-features-to-3b7dr4u3.pdf

Evaluation of Women’s Age and Ultrasonographic Features to Choose Surgical Treatment for Endometriosis Associated with Ovarian Cancer

To assess the current literature evaluating the epigenetics of endometriosis in humans.A systematic review was conducted in accordance with the PRISMA guidelines within PubMed, EBSCOhost, Cochrane Library, Embase, Scopus, and Web of Science Core Collection. A comprehensive search strategy was developed by a data informationist. Observational and interventional studies assessing epigenetics in humans published in English up to January 15th, 2023, were included. Two reviewers independently screened studies evaluating the role of epigenetics in endometriosis. The risk of bias was assessed using Cochrane RoB 2.0 tool and the Newcastle-Ottawa scale. Extracted data were analyzed descriptively.We identified 18.639 studies, of which 57 were included, comprising 1.623 patients with endometriosis and 1.243 controls. Among the 57 studies included, 50 (88%) were case-control studies, and 7 (12%) were cross-sectional. Fifty-nine percent of the studies were Asian, 25% were from America, 14% were European, and 2% were from Africa. Acetylation and methylation were the two main key histone modifications that were centered in this review. Accordingly, we classified the studies as those focusing on genome-wide methylation and those on histone acetylation. Several studies identified an association between endometriosis and hypermethylated genes, including the PGR-B, SF-1, and RASSF1A. The genes HOXA10, COX-2, IL-12B, and GATA6 were found to be hypomethylated in endometriotic tissue by several studies. In regards to histone modification, multiple studies reported that the acetylation levels of histones H3 and H4 affect multiple genes associated with endometriosis. In addition, HDAC2 was found to be elevated in endometriosis patients in two studies.Several studies reported a significant difference between specific genes' methylation levels in endometrial biopsies and normal tissue, which suggests that DNA methylation may play an important role in the modulation of the genotype in endometriotic tissue. Acetylation and methylation are the two key histone modifications leading to differential gene expression in endometriotic tissues. The alterations in gene expression reported by the 57 studies can have direct implications on cell cycle growth, cell cycle arrest, and apoptosis and, therefore, might play a key role in the pathogenesis of endometriosis. This review offers insight that histone modifications need further research to evaluate their role as potential biomarkers and treatment targets for endometriosis. Although several key similarities were reported, there were some disagreements among the results, which might be attributable to the heterogeneity between studies. Further research with a more robust standardization is needed to validate the epigenetic changes in endometriosis. 

A Systematic Review of Epigenetics of Endometriosis

Research question What is the mechanism of hypermethylation of runt-related transcription factor 3 (RUNX3) in the eutopic endometrium of endometriosis as biomarker in the malignant transformation of endometriosis? Design Methylation-specific polymerase chain reaction was used to analyse the methylation status of RUNX3 in endometriosis-associated ovarian cancer (EAOC). Primary eutopic endometrial stromal cells (ESC) were isolated from the uteri of patients with ovarian endometriosis. After RUNX3 knockdown by RNA interference technology or ESC treated with oestradiol, the proliferation and invasion ability were evaluated in ESC by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and transwell assays. Results The frequency of methylation of RUNX3 in neoplastic tissue in the EAOC group was significantly higher than that in the ectopic endometrium of the endometriosis group (P Conclusion This study demonstrated that hypermethylation of the RUNX3 was related to the malignant transformation of endometriosis and that this process was related to corresponding changes in the eutopic endometrium. Furthermore, the 'oestrogen-DNMT1' signalling pathway may induce the hypermethylation of RUNX3 to promote the malignant transformation of endometriosis.

Oestrogen up-regulates DNMT1 and leads to the hypermethylation of RUNX3 in the malignant transformation of ovarian endometriosis

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Oestrogen up-regulates DNMT1 and leads to the hypermethylation of RUNX3 in the malignant transformation of ovarian endometriosis