Variants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits.
Ontology highlight
ABSTRACT:
SUBMITTER: Rafnar T
PROVIDER: S-EPMC6128903 | biostudies-literature | 2018 Sep
REPOSITORIES: biostudies-literature
Publications
Variants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits.
Rafnar Thorunn T Gunnarsson Bjarni B Stefansson Olafur A OA Sulem Patrick P Ingason Andres A Frigge Michael L ML Stefansdottir Lilja L Sigurdsson Jon K JK Tragante Vinicius V Steinthorsdottir Valgerdur V Styrkarsdottir Unnur U Stacey Simon N SN Gudmundsson Julius J Arnadottir Gudny A GA Oddsson Asmundur A Zink Florian F Halldorsson Gisli G Sveinbjornsson Gardar G Kristjansson Ragnar P RP Davidsson Olafur B OB Salvarsdottir Anna A Thoroddsen Asgeir A Helgadottir Elisabet A EA Kristjansdottir Katrin K Ingthorsson Orri O Gudmundsson Valur V Geirsson Reynir T RT Arnadottir Ragnheidur R Gudbjartsson Daniel F DF Masson Gisli G Asselbergs Folkert W FW Jonasson Jon G JG Olafsson Karl K Thorsteinsdottir Unnur U Halldorsson Bjarni V BV Thorleifsson Gudmar G Stefansson Kari K
Nature communications 20180907 1
Uterine leiomyomas are common benign tumors of the myometrium. We performed a meta-analysis of two genome-wide association studies of leiomyoma in European women (16,595 cases and 523,330 controls), uncovering 21 variants at 16 loci that associate with the disease. Five variants were previously reported to confer risk of various malignant or benign tumors (rs78378222 in TP53, rs10069690 in TERT, rs1800057 and rs1801516 in ATM, and rs7907606 at OBFC1) and four signals are located at established r ...[more]
Similar Datasets
Project description:The purpose of this work was to engineer polymeric nanoparticles to encapsulate and deliver 2-methoxyestradiol, a potential antitumor drug for treatment of uterine leiomyoma (fibroids), the most common hormone-dependent pathology affecting women of reproductive age.Encapsulation efficiency and drug release from the nanoparticles were monitored by HPLC. Cell morphology and in vitro cytotoxicity experiments were carried out in a human leiomyoma cell line. The nanoparticles displayed high encapsulation efficiency (>86%), which was verified by differential scanning calorimetry and x-ray diffraction. Excellent long-term stability of the nanoparticles and gradual drug release without burst were also observed. Cellular uptake of fluorescent nanoparticles was confirmed by confocal imaging. The drug-loaded poly(lactic acid) and poly(lactic-co-glycolic acid) nanoparticles induced cytotoxicity in human leiomyoma cells to a significantly greater extent than the free drug at 0.35 µM.This novel approach represents a potential fertility-preserving alternative to hysterectomy.
| S-EPMC3754434 | biostudies-literature
Project description:Uterine fibroids (leiomyoma), the benign tumors of the uterine wall, are very common cause of morbidity in reproductive age women usually in the form of excessive vaginal bleeding, chronic pelvic pain, miscarriage and infertility. These tumors are the leading indication for hysterectomy in the United States. Uterine fibroids are about 4 times higher in blacks compared to whites and constitute a major health disparity challenge. The estimated cost of uterine fibroids is up to $34.4 billion annually. Additionally, women who suffer from this disease and desire to maintain their future fertility have very limited treatment choices. Currently, there is no effective long-term medicinal treatment for uterine fibroids. While surgery has traditionally been the gold standard for the treatment of uterine fibroids, there is growing interest towards orally administered medications for the management of leiomyoma-related symptoms. In this paper, we will discuss these promising innovative oral medical treatments in detail.
| S-EPMC3306913 | biostudies-other
Project description:Chronic sleep disturbances, associated with cardiometabolic diseases, psychiatric disorders and all-cause mortality, affect 25-30% of adults worldwide. Although environmental factors contribute substantially to self-reported habitual sleep duration and disruption, these traits are heritable and identification of the genes involved should improve understanding of sleep, mechanisms linking sleep to disease and development of new therapies. We report single- and multiple-trait genome-wide association analyses of self-reported sleep duration, insomnia symptoms and excessive daytime sleepiness in the UK Biobank (n = 112,586). We discover loci associated with insomnia symptoms (near MEIS1, TMEM132E, CYCL1 and TGFBI in females and WDR27 in males), excessive daytime sleepiness (near AR-OPHN1) and a composite sleep trait (near PATJ (INADL) and HCRTR2) and replicate a locus associated with sleep duration (at PAX8). We also observe genetic correlation between longer sleep duration and schizophrenia risk (rg = 0.29, P = 1.90 × 10-13) and between increased levels of excessive daytime sleepiness and increased measures for adiposity traits (body mass index (BMI): rg = 0.20, P = 3.12 × 10-9; waist circumference: rg = 0.20, P = 2.12 × 10-7).
| S-EPMC5491693 | biostudies-literature
Project description:BACKGROUND:Uterine leiomyomas, the most common tumors of the female reproductive system, are characterized by excessive deposition of disordered stiff extracellular matrix and fundamental alteration in the mechanical signaling pathways. Specifically, these alterations affect the normal dynamic state of responsiveness to mechanical cues in the extracellular environment. These mechanical cues are converted through integrins, cell membrane receptors, to biochemical signals including cytoskeletal signaling pathways to maintain mechanical homeostasis. Leiomyoma cells overexpress β1 integrin and other downstream mechanical signaling proteins. We previously reported that simvastatin, an antihyperlipidemic drug, has antileiomyoma effects through cellular, animal model, and epidemiologic studies. OBJECTIVE:This study aimed to examine the hypothesis that simvastatin might influence altered mechanotransduction in leiomyoma cells. STUDY DESIGN:This is a laboratory-based experimental study. Primary leiomyoma cells were isolated from 5 patients who underwent hysterectomy at the Department of Gynecology and Obstetrics of the Johns Hopkins University Hospital. Primary and immortalized human uterine leiomyoma cells were treated with simvastatin at increasing concentrations (0.001, 0.01, 0.1, and 1 μM, or control) for 48 hours. Protein and mRNA levels of β1 integrin and extracellular matrix components involved in mechanical signaling were quantified by quantitative real-time polymerase chain reaction, western blotting, and immunofluorescence. In addition, we examined the effect of simvastatin on the activity of Ras homolog family member A using pull-down assay and gel contraction. RESULTS:We found that simvastatin significantly reduced the protein expression of β1 integrin by 44% and type I collagen by 60% compared with untreated leiomyoma cells. Simvastatin-treated cells reduced phosphorylation of focal adhesion kinase down to 26%-60% of control, whereas it increased total focal adhesion kinase protein expression. Using a Ras homolog family member A pull-down activation assay, we observed reduced levels of active Ras homolog family member A in simvastatin-treated cells by 45%-85% compared with control. Consistent with impaired Ras homolog family member A activation, simvastatin treatment reduced tumor gel contraction where gel area was 122%-153% larger than control. Furthermore, simvastatin treatment led to reduced levels of mechanical signaling proteins involved in β1 integrin downstream signaling, such as A-kinase anchor protein 13, Rho-associated protein kinase 1, myosin light-chain kinase, and cyclin D1. CONCLUSION:The results of this study suggest a possible therapeutic role of simvastatin in restoring the altered state of mechanotransduction signaling in leiomyoma. Collectively, these findings are aligned with previous epidemiologic studies and other reports and support the need for clinical trials.
| S-EPMC7609626 | biostudies-literature
Project description:Uterine leiomyomas, or fibroids, are the most common human tumors. Based on histopathology, they can be divided into common leiomyomas and various relatively rare subtypes that mimic malignancy in one or more aspects. Recently, we showed that exon 2 of mediator complex subunit 12 (MED12) is mutated in up to 70% of common fibroids. To investigate the frequency of MED12 exon 2 mutations in histopathological uterine leiomyoma variants, we screened altogether 206 lesions, including 69 histopathologically common leiomyomas, 59 cellular (23 cellular and 36 highly cellular), 18 atypical and 26 mitotically active leiomyomas, as well as 34 uterine fibroid samples from 14 hereditary leiomyomatosis and renal cell cancer patients with a heterozygous germ line mutation in fumarate hydratase (FH). The uterine leiomyoma variants harbored MED12 exon 2 mutations significantly less frequently than common leiomyomas (P=2.93 × 10(-8)). In all, 6 mutations were detected among cellular fibroids (6/67; 8.96%), 3 among atypical fibroids (3/18; 16.67%) and 10 among mitotically active fibroids (10/26; 38.46%). Only mitotically active fibroids displayed a mutation frequency that was not statistically different from common leiomyomas (P=0.11). Three MED12 exon 2 mutations were detected among 34 tumors with a heterozygous germ line FH mutation (P=5.28 × 10(-7)). None of these tumors displayed biallelic inactivation of FH. Our results suggest that MED12 mutation positivity is a key characteristic of common leiomyomas. Cellular and atypical fibroids, in particular, may arise through different molecular mechanisms. The results also propose that MED12 and biallelic FH mutations may be mutually exclusive.
| S-EPMC3798840 | biostudies-literature
Project description:BackgroundUterine leiomyoma is the most common benign tumor in reproductive-age women. Each leiomyoma is thought to be a benign monoclonal tumor arising from a single transformed myometrial smooth muscle cell; however, it is not known what leiomyoma cell type is responsible for tumor growth. Thus, we tested the hypothesis that a distinct stem/reservoir cell-enriched population, designated as the leiomyoma-derived side population (LMSP), is responsible for cell proliferation and tumor growth.Principal findingsLMSP comprised approximately 1% of all leiomyoma and 2% of all myometrium-derived cells. All LMSP and leiomyoma-derived main population (LMMP) but none of the side or main population cells isolated from adjacent myometrium carried a mediator complex subunit 12 mutation, a genetic marker of neoplastic transformation. Messenger RNA levels for estrogen receptor-α, progesterone receptor and smooth muscle cell markers were barely detectable and significantly lower in the LMSP compared with the LMMP. LMSP alone did not attach or survive in monolayer culture in the presence or absence of estradiol and progestin, whereas LMMP readily grew under these conditions. LMSP did attach and survive when directly mixed with unsorted myometrial cells in monolayer culture. After resorting and reculturing, LMSP gained full potential of proliferation. Intriguingly, xenografts comprised of LMSP and unsorted myometrial smooth muscle cells grew into relatively large tumors (3.67 ± 1.07 mm(3)), whereas xenografts comprised of LMMP and unsorted myometrial smooth muscle cells produced smaller tumors (0.54 ± 0.20 mm(3), p<0.05, n = 10 paired patient samples). LMSP xenografts displayed significantly higher proliferative activity compared with LMMP xenografts (p<0.05).ConclusionsOur data suggest that LMSP, which have stem/reservoir cell characteristics, are necessary for in vivo growth of leiomyoma xenograft tumors. Lower estrogen and progesterone receptor levels in LMSP suggests an indirect paracrine effect of steroid hormones on stem cells via the mature neighboring cells.
| S-EPMC3343011 | biostudies-literature
Project description:Leiomyoma are common tumors arising within the uterus that feature excessive deposition of a stiff, disordered extracellular matrix (ECM). Mechanical stress is a critical determinant of excessive ECM deposition and increased mechanical stress has been shown to be involved in tumorigenesis. Here we tested the viscoelastic properties of leiomyoma and characterized dynamic and static mechanical signaling in leiomyoma cells using three approaches, including measurement of active RhoA. We found that the peak strain and pseudo-dynamic modulus of leiomyoma tissue was significantly increased relative to matched myometrium. In addition, leiomyoma cells demonstrated an attenuated response to applied cyclic uniaxial strain and to variation in substrate stiffness, relative to myometrial cells. However, on a flexible pronectin-coated silicone substrate, basal levels and lysophosphatidic acid-stimulated levels of activated RhoA were similar between leiomyoma and myometrial cells. In contrast, leiomyoma cells plated on a rigid polystyrene substrate had elevated levels of active RhoA, compared to myometrial cells. The results indicate that viscoelastic properties of the ECM of leiomyoma contribute significantly to the tumor's inherent stiffness and that leiomyoma cells have an attenuated sensitivity to mechanical cues. The findings suggest there may be a fundamental alteration in the communication between the external mechanical environment (extracellular forces) and reorganization of the actin cytoskeleton mediated by RhoA in leiomyoma cells. Additional research will be needed to elucidate the mechanism(s) responsible for the attenuated mechanical signaling in leiomyoma cells.
| S-EPMC3576015 | biostudies-literature
Project description:Somatic mutations in exon 2 of the RNA polymerase II transcriptional Mediator subunit MED12 occur at very high frequency (?70%) in uterine leiomyomas. However, the influence of these mutations on Mediator function and the molecular basis for their tumorigenic potential remain unknown. To clarify the impact of these mutations, we used affinity-purification mass spectrometry to establish the global protein-protein interaction profiles for both wild-type and mutant MED12. We found that uterine leiomyoma-linked mutations in MED12 led to a highly specific decrease in its association with Cyclin C-CDK8/CDK19 and loss of Mediator-associated CDK activity. Mechanistically, this occurs through disruption of a MED12-Cyclin C binding interface that we also show is required for MED12-mediated stimulation of Cyclin C-dependent CDK8 kinase activity. These findings indicate that uterine leiomyoma-linked mutations in MED12 uncouple Cyclin C-CDK8/19 from core Mediator and further identify the MED12/Cyclin C interface as a prospective therapeutic target in CDK8-driven cancers.
| S-EPMC4041330 | biostudies-literature
Project description:BACKGROUND: Uterine leiomyomas (fibroids) are the most common gynaecological benign tumors in premenopausal women. Evidences support the role of oxidative stress in the development of uterine leiomyoma. We have analysed oxidative stress markers (thiols, advanced oxidized protein products (AOPP), protein carbonyls and nitrates/nitrites) in preoperative sera from women with histologically proven uterine leiomyoma. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a laboratory study in a tertiary-care university hospital. Fifty-nine women with histologically proven uterine leiomyoma and ninety-two leiomyoma-free control women have been enrolled in this study. Complete surgical exploration of the abdominopelvic cavity was performed in each patient. Preoperative serum samples were obtained from all study participants to assay serum thiols, AOPP, protein carbonyls and nitrates/nitrites. Concentrations of serum protein carbonyl groups and AOPP were higher in leiomyoma patients than in the control group (p=0.005 and p<0.001, respectively). By contrast, serum thiol levels were lower in leiomyoma patients (p<0.001). We found positive correlations between serum AOPP concentrations and total fibroids weight (r=0.339; p=0.028), serum AOPP and serum protein carbonyls with duration of infertility (r=0.762; p=0.006 and r=0.683; p=0.021, respectively). CONCLUSIONS/SIGNIFICANCE: This study, for the first time, reveals a significant increase of protein oxidative stress status and reduced antioxidant capacity in sera from women with uterine leiomyoma.
| S-EPMC3739822 | biostudies-literature
Project description:OBJECTIVE:To retrospectively assess conventional magnetic resonance imaging (MRI) features that differentiate malignant pure mesenchymal uterine tumors (MPMUT); endometrial stromal sarcoma (ESS) and leiomyosarcoma (LMS) from uterine leiomyoma with cystic degeneration (ULCD). METHODS:We retrospectively reviewed magnetic resonance (MR) images of 30 patients with ULCD, 18 with ESS, and 15 with LMS, to assess tumor location, margin, T2 signal intensity (SI), speckled appearance, and peripheral band using univariate and multivariate analyses. RESULTS:ULCD more frequently showed subserosal location (53.3%), well-defined margin (96.7%), and speckled appearance (90.0%) compared with ESS (0%, 33.3%, and 33.3%, respectively) or LMS (20.0%, 33.3%, and 60.0%, respectively). In quantitative T2 SI comparisons, the T2 SI ratio of the main solid tumor portion to gluteus maximus muscle differed significantly among the three groups, with ULCD showing a lower SI ratio (0.62) compared with ESS (2.44) and LMS (1.13). On multivariate analysis, an ill-defined margin (odds ratio [OR]=44.885; p=0.003) and high T2 SI (OR=4.396; p=0.046) were the significant MR differentiators. CONCLUSION:An ill-defined tumor margin and high T2 SI ratio of the main solid tumor-to-gluteus maximus muscle were useful MRI features in the differentiation of MPMUT from ULCD.
| S-EPMC5920213 | biostudies-literature