Mediator Kinase Disruption in MED12-Mutant Uterine Fibroids From Hispanic Women of South Texas.
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ABSTRACT:
SUBMITTER: Park MJ
PROVIDER: S-EPMC6194812 | biostudies-other | 2018 Nov
REPOSITORIES: biostudies-other
Publications
Mediator Kinase Disruption in MED12-Mutant Uterine Fibroids From Hispanic Women of South Texas.
Park Min Ju MJ Shen Hailian H Kim Nam Hee NH Gao Fangjian F Failor Courtney C Knudtson Jennifer F JF McLaughlin Jessica J Halder Sunil K SK Heikkinen Tuomas A TA Vahteristo Pia P Al-Hendy Ayman A Schenken Robert S RS Boyer Thomas G TG
The Journal of clinical endocrinology and metabolism 20181101 11
<h4>Context</h4>Mutations in the gene encoding Mediator complex subunit MED12 are dominant drivers of uterine fibroids (UFs) in women of diverse racial and ethnic origins. Previously, we showed that UF-linked mutations in MED12 disrupt its ability to activate cyclin C-CDK8/19 in Mediator. However, validation of Mediator kinase disruption in the clinically relevant setting of MED12-mutant UFs is currently lacking.<h4>Objective</h4>The objective of this study was twofold. First, to extend the ethn ...[more]
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Project description:Unintended birth is associated with adverse maternal and infant outcomes. In 2006, US Hispanics had the highest unintended birth rate (45 births/1,000 women) compared to other groups. One-fifth of US Hispanic women reside in Texas, yet unintended birth among Texas Hispanics has not been studied. The goal of this study was to describe the prevalence and characteristics of unintended birth in this population. Using data from Hispanic participants in the Texas Pregnancy Risk Assessment Monitoring System 2009-2010, we studied unintended birth in relation to demographic, lifestyle and partner characteristics. Adjusted prevalence odds ratios (POR) were computed for each characteristic and the analysis was stratified by maternal nativity (US vs foreign born). The weighted proportion of unintended birth was 49.5 % (CI = 45.9-52.6). In adjusted analyses, women aged 12-19 had a higher prevalence of unintended birth compared to ?20 years (POR = 2.1, CI = 1.3-3.7). Unmarried (POR = 1.5, CI = 1.1-2.1), uninsured (POR = 1.7, CI = 1.2-2.3), and US-born (POR = 1.6, CI = 1.0-2.6) women had higher prevalence compared to married, insured and foreign-born women, respectively. Among US-born Hispanic women, higher prevalence of unintended birth was associated with being young, unmarried and experiencing psychological stressors within 12 months of giving birth; among foreign-born Hispanic women, higher prevalence was associated with lack of insurance. Efforts to reduce unintended birth in Texas might focus on young, single, uninsured and US-born Hispanic women. Analyses of other pre-pregnancy factors and health outcomes among Texas Hispanics could increase understanding of the differences we observed in unintended birth between US and foreign-born Hispanics.
| S-EPMC4418950 | biostudies-other
Project description:Uterine fibroid (UF) driver mutations in Mediator complex subunit 12 (MED12) trigger genomic instability and tumor development through unknown mechanisms. Herein, we show that MED12 mutations trigger aberrant R-loop-induced replication stress, suggesting a possible route to genomic instability and a novel therapeutic vulnerability in this dominant UF subclass. Immunohistochemical analyses of patient-matched tissue samples revealed that MED12 mutation-positive UFs, compared to MED12 mutation-negative UFs and myometrium, exhibited significantly higher levels of R-loops and activated markers of Ataxia Telangiectasia and Rad3-related (ATR) kinase-dependent replication stress signaling in situ. Single molecule DNA fiber analysis revealed that primary cells from MED12 mutation-positive UFs, compared to those from patient-matched MED12 mutation-negative UFs and myometrium, exhibited defects in replication fork dynamics, including reduced fork speeds, increased and decreased numbers of stalled and restarted forks, respectively, and increased asymmetrical bidirectional forks. Notably, these phenotypes were recapitulated and functionally linked in cultured uterine smooth muscle cells following chemical inhibition of Mediator-associated CDK8/19 kinase activity that is known to be disrupted by UF driver mutations in MED12. Thus, Mediator kinase inhibition triggered enhanced R-loop formation and replication stress leading to an S-phase cell cycle delay, phenotypes that were rescued by overexpression of the R-loop resolving enzyme RNaseH. Altogether, these findings reveal MED12-mutant UFs to be uniquely characterized by aberrant R-loop induced replication stress, suggesting a possible basis for genomic instability and new avenues for therapeutic intervention that involve the replication stress phenotype in this dominant UF subtype.
| S-EPMC9008039 | biostudies-literature
Project description:BackgroundUterine fibroids are the most common benign uterine tumours present in women of reproductive age. Mifepristone (RU-486) competitively binds and inhibits progesterone receptors. Studies have suggested that fibroid growth depends on the sexual steroids. Mifepristone has been shown to decrease fibroid size. This review summarises the effects of mifepristone treatment on fibroids and the associated adverse effects as described in randomised controlled trials.ObjectivesTo determine the efficacy and safety of mifepristone for the management of uterine fibroids in pre-menopausal women.Search methodsWe searched the specialised register of the Cochrane Menstrual Disorders and Subfertility (Cochrane Menstrual Disorders and subfertility Review Group), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 4), MEDLINE, EMBASE, PsycINFO, and CINAHL (to November 2011). We handsearched a number of journals, and searched reference lists, databases of ongoing trials and the Internet. There were no language restrictions.Selection criteriaOnly truly randomised controlled trials of mifepristone versus other forms of medical therapy or placebo in pre-menopausal women with confirmed uterine fibroids were included.Data collection and analysisFour authors independently extracted data and assessed trial quality. Data were analysed using the Peto odds ratios (OR) for dichotomous data and the weighted mean differences for continuous data, with 95% confidence intervals (CI). Meta-analyses were performed using the fixed-effect model.Main resultsThree studies involving 112 participants were included. Comparison interventions included different dosages of mifepristone, placebo and vitamin B tablets. There is evidence that treatment with mifepristone relieves heavy menstrual bleeding compared with placebo (Peto OR 17.84; 95% CI 6.72 to 47.38; 2 RCTs, 77 women, I(2) = 0%). Three studies (Bagaria 2009; Engman 2009; Fiscella 2006) were included in the meta-analysis of this comparison. There was no evidence of an effect of mifepristone on the fibroid volume (standardised mean difference (SMD) -0.02; 95% CI -0.38 to 0.41; 99 women). Two studies (Bagaria 2009; Fiscella 2006) were included in the meta-analysis of this comparison. There was no evidence of an effect of mifepristone on uterine volume (mean difference (MD) -77.24; 95% CI -240.62 to 86.14; 72 women). The pooled data suggest an increased adverse event (abnormal endometrial histology) in the mifepristone group compared to placebo (OR 31.65; 95% CI 4.83 to 207.35; 2 RCTs; 54 women; I(2) = 0%). Only one study (Bagaria 2009) reported endometrial hyperplasia at the end of the therapy (12/19 women in the mifepristone group versus 0/16 in the placebo group; OR 55.0; 95% CI 2.86 to 105.67). Engman 2009 found a significantly higher rate of cystic glandular dilatation in women in the mifepristone group (5/8 women biopsied) compared with the placebo group (1/11 women biopsied) (OR 16.67; 95% CI 1.36 to 204.03). One study (Fiscella 2006) suggested significant improvements (P < 0.001) for specific quality of life outcomes.Authors' conclusionsMifepristone reduced heavy menstrual bleeding and improved fibroid-specific quality of life. However, it was not found to reduce fibroid volume. Further well-designed, adequately powered RCTs are needed before a recommendation can be made on the use of mifepristone for the treatment of uterine fibroids.
| S-EPMC8212859 | biostudies-literature
Project description:Uterine fibroids are a major cause of morbidity in women of a reproductive age (and sometimes even after menopause). There are several factors that are attributed to underlie the development and incidence of these common tumors, but this further corroborates their relatively unknown etiology. The most likely presentation of fibroids is by their effect on the woman's menstrual cycle or pelvic pressure symptoms. Leiomyosarcoma is a very rare entity that should be suspected in postmenopausal women with fibroid growth (and no concurrent hormone replacement therapy). The gold standard diagnostic modality for uterine fibroids appears to be gray-scale ultrasonography, with magnetic resonance imaging being a close second option in complex clinical circumstances. The management of uterine fibroids can be approached medically, surgically, and even by minimal access techniques. The recent introduction of selective progesterone receptor modulators (SPRMs) and aromatase inhibitors has added more armamentarium to the medical options of treatment. Uterine artery embolization (UAE) has now been well-recognized as a uterine-sparing (fertility-preserving) method of treating fibroids. More recently, the introduction of ultrasound waves (MRgFUS) or radiofrequency (VizAblate™ and Acessa™) for uterine fibroid ablation has added to the options of minimal access treatment. More definite surgery in the form of myomectomy or hysterectomy can be performed via the minimal access or open route methods. Our article seeks to review the already established information on uterine fibroids with added emphasis on contemporary knowledge.
| S-EPMC3914832 | biostudies-other
Project description:BackgroundMost women will experience uterine fibroids by the age of 50, yet few data exist describing the overall patient experience with fibroids. The objective of this population-based survey was to characterize symptom burden, patient awareness, and treatment decision-making for fibroids, including a comparison among women of varying backgrounds.Materials and methodsWomen (?18 years) were recruited via email from GfK KnowledgePanel®, a representative panel of US households, or identified with opt-in consumer panels. The Uterine Fibroid Symptom and Health-Related Quality of Life (UFS-QOL) questionnaire and Aberdeen Menorrhagia Severity Scale (AMSS) were included.ResultsEligible women were grouped into three cohorts: "at-risk" (symptoms suggestive of fibroids without clinical diagnosis, n?=?300), "diagnosed" (n?=?871), and fibroid-related "hysterectomy" (n?=?272). Cohort and intracohort race/ethnicity and income analyses revealed differences in symptom burden, awareness/perception, and treatment history. Based on UFS-QOL scores, at-risk women reported significantly greater symptom severity and decreased health-related QOL versus diagnosed women; Hispanic women reported greater symptom severity versus white and black women. At-risk women also reported heavy menstrual bleeding and significant impact on work productivity. Among diagnosed women, 71% used pharmacologic therapy for symptom relief, and 30% underwent surgical or procedural treatment. Initial discussions with healthcare providers significantly impacted treatment outcomes; the hysterectomy cohort was most likely to first discuss hysterectomy.ConclusionsWomen with fibroids or symptoms suggestive of fibroids experience significant distress that reduces QOL, particularly racial minorities and women in lower income brackets. Survey results suggest that many women are likely undiagnosed, underscoring the need for improved awareness and education.
| S-EPMC6247381 | biostudies-literature
Project description:Women with fibroids have a notably high hypertension risk. However, adjusted data regarding other cardiovascular disease (CVD) risk factors are scarce. In this cross-sectional study, CVD risk factors, hemodynamic parameters, and asymptomatic organ damage were analyzed between women with uterine fibroids and controls in a multi-ethnic population. In total, 104 women with self-reported fibroids and 624 controls were included. Women with fibroids had significantly higher odds to have hypertension (OR 3.4; 95% CI 2.2-5.2), diabetes (1.7; 1.0-2.9), and hypercholesterolemia (1.8; 1.1-3.2). After adjustment for confounders, only the odds ratio for hypertension was significant (1.8; 1.1-3.1). Asymptomatic organ damage occurred significantly more often in women with fibroids (66.7%; 95% CI 55.8%-77.6% vs 42.9%; 38.0-47.8 in controls), especially in the younger age group (respectively 48.5%; 31.1%-65.9% vs 22.1%; 17.0-27.2). In this study, women with fibroids had a remarkably high hypertension risk compared to controls, with more asymptomatic organ damage, in particular young women.
| S-EPMC8030762 | biostudies-literature
Project description:ObjectiveTo evaluate the extent to which uterine fibroids are associated with antimüllerian hormone (AMH) concentrations.DesignCross-sectional study.SettingBaseline data from the Study of the Environment, Lifestyle, and Fibroids, which is a 5-year longitudinal study of African American women.Patient(s)A total of 1,643 women aged 23-35 years without a known history of fibroids.ExposureFibroid presence.Intervention(s)None.Main outcome measure(s)The primary outcome was percent difference in the mean AMH concentration between participants with fibroids and those without fibroids. The secondary outcomes were percent differences in the mean AMH concentrations in participants with different numbers, sizes, types, and positions of fibroids and the percent difference in the mean AMH concentration in participants with different uterine volumes.Result(s)At least 1 fibroid was identified on ultrasound in 362 (22%) participants. There was a small difference in the mean AMH concentrations in participants with fibroids (age-adjusted model: -4.6%, 95% confidence interval (CI): -14.5% to 6.5%; multivariable model: -4.6%, 95% CI: -14.4% to 6.3%). The mean AMH concentrations were found to decrease with increasing fibroid number. Although differences in AMH concentrations were not statistically significant, compared with no fibroids, the mean percent differences in AMH concentrations for 1, 2-3, and ≥4 fibroids were -1.2% (95% CI: -13.2% to 12.5%), -7.1% (95% CI: -23.3% to 12.5%), and -17.5% (95% CI: -38.2% to 10.0%), respectively. There were no consistent associations between AMH concentrations and fibroid location, size, or uterine volume.Conclusion(s)The presence of fibroids was not materially associated with AMH concentrations. Other than a monotonic inverse relationship between fibroid number and AMH concentrations, no other fibroid characteristics were consistently or appreciably associated, although associations were imprecise.
| S-EPMC8983564 | biostudies-literature
Project description:BackgroundUterine fibroids are the most common non-malignant growths in women of childbearing age. They are associated with heavy menstrual bleeding and subfertility. Herbal preparations are commonly used as alternatives to surgical procedures.ObjectivesTo assess the benefits and risks of herbal preparations for uterine fibroids.Search strategyAuthors searched following electronic databases: the Trials Registers of the Cochrane Menstrual Disorders and Subfertility Group and the Cochrane Complementary Medicine Field, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, Issue 3), MEDLINE, EMBASE, the Chinese Biomedical Database, the Traditional Chinese Medical Literature Analysis and Retrieval System (TCMLARS), AMED, and LILACS. The searches ended on 31st December 2008.Selection criteriaRandomised controlled trials comparing herbal preparations with no intervention, placebo, medical treatment or surgical procedures in women with uterine fibroids. We also included trials of herbal preparations with or without conventional therapy.Data collection and analysisTwo review authors collected data independently. We assessed trial risk of bias according to our methodological criteria . We presented dichotomous data as risk ratios (RR) and continuous outcomes as mean difference (MD), both with 95% confidence intervals (CI).Main resultsWe included two randomised trials (involved 150 women) with clear description of randomisation methods. The methodological risk of bias of the trials varied. There were variations in the tested herbal preparations, and the treatment duration was six months. The outcomes available were not the primary outcomes selected for this review, such as symptom relief or the need for surgical treatment; trials mainly reported outcomes in terms of shrinkage of the fibroids.Compared with mifepristone, Huoxue Sanjie decoction showed no significant difference in the disappearance of uterine fibroids, number of patients with shrinking of uterine fibroids or average volume of uterine fibroids, but less effective than mifepristone on reducing average size of uterus (mean difference 23.23 cm(3),95% confidence interval 17.85 to 28.61). There was no significant difference between Nona Roguy herbal product and GnRH agonist in average volume of uterine fibroids or size of uterus. No serious adverse effects from herbal preparations was reported.Authors' conclusionsCurrent evidence does not support or refute the use of herbal preparations for treatment of uterine fibroids due to insufficient studies of large sample and high quality. Further high quality trials evaluating clinically relevant outcomes are warranted.
| S-EPMC3155698 | biostudies-literature
Project description:We review recent studies dealing with the molecular genetics and basic results of omics analysis of uterine leiomyoma (LM)-a common benign muscle tumor of the uterus. Whole genome studies of LM resulted in the discovery of many new gene nets and biological pathways, including its origin, transcriptomic, and epigenetic profiles, as well as the impact of the inter-cell matrix in LM growth and involvement of microRNA in its regulation. New data on somatic cell mutations ultimately involved in the origin, distribution and growth of LM are reviewed. Putative identification of LM progenitor SC (stem cells) giving rise to maternal fibroid nodes and junctional zones provide a new clue for hypotheses on the pathogenomics of LM. The reviewed data are consistent with at least two different but probably intimately interacted molecular mechanisms of LM. One of them (the genetic hypothesis) is focused primarily on the MED12 gene mutations and suggests its onset in the side population of embryonic myoblasts of the female reproductive system, which later gave rise to multiple small and medium fibroids. The single and usually large-size fibroids are induced by predominantly epigenetic disorders in LM SC, provoked by enhanced expression of the HMGA2 gene caused by its hypomethylation and epigenetic deregulation enhanced by hypoxia, muscle tension, or chromosome instability/aberrations. The pathogenomics of both genetic and epigenetic programs of LM with many peculiarities at the beginning later became rather similar and partly overlapped due to the proximity of their gene nets and epigenetic landscape. Pathogenomic studies of LM open ways for elaboration of novel strategies of prevention and treatment of this common disease.
| S-EPMC6940759 | biostudies-literature
Project description:Uterine fibroids (UFs, AKA leiomyoma) are the most important benign neoplastic threat to women's health, with costs up to hundreds of billions of health care dollars worldwide. Uterine fibroids caused morbidities exert a tremendous health toll, impacting the quality of life of women of all ethnicities, especially women of color. Clinical presentations include heavy vaginal bleeding, pelvic pain, bulk symptoms, subfertility, and obstetric complications. Current management strategies heavily lean toward surgical procedures; nonetheless, the choice of treatment is generally subject to patient's age and her desire to preserve future fertility. Women with UF who desire to maintain future fertility potential face a dilemma because of the limited treatment choices that are currently available to help them achieve that goal. Recently, ulipristal acetate the first of the promising family of oral selective progesterone receptor modulators has been approved for UF treatment in Europe, Canada, and several other countries and is under review for possible approval in the USA. In this review article, we discuss recent advances in the management options against UF with a bend toward oral effective long-term treatment alternatives who are particularly suited for those seeking to preserve their future fertility potential. We also explore the transformative concept of primary and secondary UF prevention using these new anti-UF agents. We envision a remarkable shift in the management of UF in future years from surgical/invasive treatment to orally administrated options; clearly, this potential shift will require additional intense clinical research.
| S-EPMC5803778 | biostudies-other