RESUMO
Objective: To assess the current literature evaluating the epigenetics of endometriosis in humans. Evidence Review: 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. Results: 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. Conclusion: 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.
RESUMO
Uterine leiomyomas are the most common tumor of reproductive-age women worldwide. Although benign, uterine fibroids cause significant morbidity and adversely impact the quality of life for affected women. Somatic mutations in the exon 2 of the mediator complex subunit 12 (MED-12) gene represent the most common single gene mutation associated with uterine leiomyomas. The objective of this review was to evaluate the current role of MED-12 mutation in the pathophysiology of uterine fibroids, to assess the prevalence of MED-12 mutation among different populations, and to identify the most common subtypes of MED-12 mutations found in uterine fibroids. A comprehensive search was conducted using Pubmed, Embase, Scopus, and the Web of Science. English-language publications that evaluated MED-12 mutation and uterine fibroids in humans, whether experimental or clinical, were considered. We identified 380 studies, of which 23 were included, comprising 1353 patients and 1872 fibroid tumors. Of the total number of tumors analyzed, 1045 (55.8%) harbored a MED-12 mutation. Among the 23 studies included, the frequency of MED-12 mutation varied from 31.1 to 80% in fibroid samples. The most common type of MED-12 mutation was a heterozygous missense mutation affecting codon 44 of exon 2, specifically the nucleotide 131. Studies reported that MED-12 mutation acts by increasing levels of AKT and disrupting the cyclin C-CDK8/19 kinase activity. The overall average prevalence of MED-12 mutation in uterine fibroids was found to be 55.8% across the global population, though the frequency varied greatly among different countries.
