Uterine leiomyomas are common benign smooth muscle tumors that impose a major burden on women’s health. Recent sequencing studies have revealed recurrent and mutually exclusive mutations in ...leiomyomas, suggesting the involvement of molecularly distinct pathways. In this study, we explored transcriptional differences among leiomyomas harboring different genetic drivers, including high mobility group AT-hook 2 (HMGA2) rearrangements, mediator complex subunit 12 (MED12) mutations, biallelic inactivation of fumarate hydratase (FH), and collagen, type IV, alpha 5 and collagen, type IV, alpha 6 (COL4A5-COL4A6) deletions. We also explored the transcriptional consequences of 7q22, 22q, and 1p deletions, aiming to identify possible target genes. We investigated 94 leiomyomas and 60 corresponding myometrial tissues using exon arrays, whole genome sequencing, and SNP arrays. This integrative approach revealed subtype-specific expression changes in key driver pathways, including Wnt/β-catenin, Prolactin, and insulin-like growth factor (IGF)1 signaling. Leiomyomas with HMGA2 aberrations displayed highly significant up-regulation of the proto-oncogene pleomorphic adenoma gene 1 (PLAG1), suggesting that HMGA2 promotes tumorigenesis through PLAG1 activation. This was supported by the identification of genetic PLAG1 alterations resulting in expression signatures as seen in leiomyomas with HMGA2 aberrations. RAD51 paralog B (RAD51B), the preferential translocation partner of HMGA2, was up-regulated in MED12 mutant lesions, suggesting a role for this gene in the genesis of leiomyomas. FH-deficient leiomyomas were uniquely characterized by activation of nuclear factor erythroid 2-related factor 2 (NRF2) target genes, supporting the hypothesis that accumulation of fumarate leads to activation of the oncogenic transcription factor NRF2. This study emphasizes the need for molecular stratification in leiomyoma research and possibly in clinical practice as well. Further research is needed to determine whether the candidate biomarkers presented herein can provide guidance for managing the millions of patients affected by these lesions.
Objective To determine the frequency of mediator complex subunit 12 (MED12) mutations in well-documented, prospectively collected, unselected series of sporadic uterine leiomyomas to better ...understand the contribution of MED12 mutations in leiomyoma genesis. Design Mutation analysis of two prospectively collected sample series. Setting Department of gynecology in university hospital and medical genetics research laboratory. Patient(s) 164 uterine leiomyomas from 28 patients (13 consecutive and 15 unselected patients) undergoing hysterectomy. Intervention(s) MED12 mutation screening by direct sequencing, and clinical data collection. Main Outcome Measure(s) MED12 mutation status and various clinical variables. Result(s) MED12 mutations were found in 73 (83.0%) of 88 and 65 (85.5%) of 76 of uterine leiomyomas from the consecutive and unselected patient series, respectively. Smaller tumor size and a larger number of tumors correlated with positive MED12 mutation status. Conclusion(s) The frequency of MED12 mutations in our prospectively collected uterine leiomyoma sets was higher than in previous works. This is in keeping with the concept that MED12 mutation-positive tumors tend to be smaller in size than MED12 mutation-negative tumors. The results highlight the central role of MED12 mutations in uterine leiomyoma genesis.
Uterine leiomyomas (ULs) are benign tumors that are a major burden to women's health. A genome-wide association study on 15,453 UL cases and 392,628 controls was performed, followed by replication of ...the genomic risk in six cohorts. Effects of the risk alleles were evaluated in view of molecular and clinical characteristics. 22 loci displayed a genome-wide significant association. The likely predisposition genes could be grouped to two biological processes. Genes involved in genome stability were represented by
- highlighting the role of telomere maintenance -
and
. Genes involved in genitourinary development,
and uterine stem cell marker antigen
formed another strong subgroup. The combined risk contributed by the 22 loci was associated with
mutation-positive tumors. The findings link genes for uterine development and genetic stability to leiomyomagenesis, and in part explain the more frequent occurrence of UL in women of African origin.
Uterine leiomyomas can be classified into molecularly distinct subtypes according to their genetic triggers: MED12 mutations, HMGA2 upregulation, or inactivation of FH. The aim of this study was to ...identify metabolites and metabolic pathways that are dysregulated in different subtypes of leiomyomas.
We performed global metabolomic profiling of 25 uterine leiomyomas and 17 corresponding myometrium specimens using liquid chromatography-tandem mass spectroscopy.
A total of 641 metabolites were detected. All leiomyomas displayed reduced homocarnosine and haeme metabolite levels. We identified a clearly distinct metabolomic profile for leiomyomas of the FH subtype, characterised by metabolic alterations in the tricarboxylic acid cycle and pentose phosphate pathways, and increased levels of multiple lipids and amino acids. Several metabolites were uniquely elevated in leiomyomas of the FH subtype, including N6-succinyladenosine and argininosuccinate, serving as potential biomarkers for FH deficiency. In contrast, leiomyomas of the MED12 subtype displayed reduced levels of vitamin A, multiple membrane lipids and amino acids, and dysregulation of vitamin C metabolism, a finding which was also compatible with gene expression data.
The study reveals the metabolomic heterogeneity of leiomyomas and provides the requisite framework for strategies designed to target metabolic alterations promoting the growth of these prevalent tumours.
Uterine leiomyomas from hereditary leiomyomatosis and renal cell cancer (HLRCC) patients are driven by fumarate hydratase (FH) inactivation or occasionally by mediator complex subunit 12 (MED12) ...mutations. The aim of this study was to analyse whether MED12 mutations and FH inactivation are mutually exclusive and to determine the contribution of MED12 mutations on HLRCC patients' myomagenesis.
MED12 exons 1 and 2 mutation screening and 2SC immunohistochemistry indicative for FH deficiency was performed on a comprehensive series of HLRCC patients' (122 specimens) and sporadic (66 specimens) tumours. Gene expression analysis was performed using Affymetrix GeneChip Human Exon Arrays (Affymetrix, Santa Clara, CA, USA).
Nine tumours from HLRCC patients harboured a somatic MED12 mutation and were negative for 2SC immunohistochemistry. All remaining successfully analysed lesions (107/116) were deficient for FH. Of sporadic tumours, 35/64 were MED12 mutation positive and none displayed a FH defect. In global gene expression analysis FH-deficient tumours clustered together, whereas HLRCC patients' MED12 mutation-positive tumours clustered together with sporadic MED12 mutation-positive tumours.
Somatic MED12 mutations and biallelic FH inactivation are mutually exclusive in both HLRCC syndrome-associated and sporadic uterine leiomyomas. The great majority of HLRCC patients' uterine leiomyomas are caused by FH inactivation, but incidental tumours driven by somatic MED12 mutations also occur. These MED12 mutation-positive tumours display similar expressional profiles with their sporadic counterparts and are clearly separate from FH-deficient tumours.
► Role of FOSL1 overexpression in growth of antiestrogen-resistant breast cancer cells. ► Inhibition of FOSL1 overexpression decreased cell growth. ► Inhibition of FOSL1 increased formation of ...vacuoles followed by cell death. ► Inhibition of FOSL1 restored sensitivity to antiestrogen.
Elevated activator protein-1 (AP-1) activity in breast cancer cells has been linked to Tamoxifen (TAM) resistance. Fos-like antigen-1 (FOSL1) is a member of the AP-1 transcription factor and is overexpressed in a variety of human cancers including breast tumors. We have previously established an estrogen-independent and antiestrogen Toremifene (TOR)-resistant subline of MCF-7 breast cancer cells. In these cells, the expression of FOSL1 is upregulated when compared to the parental cells. In the present study, partial inhibition of FOSL1 expression in these cells by small interfering RNA resulted in a marked decrease of cell growth. The inhibition of cell growth paralleled with changes in cell morphology such as increased formation of vacuoles followed by an increase in the number of dead cells. The inhibition of FOSL1 expression in these cells also restored sensitivity to TOR. Our results suggest that chemotherapy targeting overexpression of FOSL1 could be a potent strategy for treating endocrine resistant breast cancers.
Adrenal infarction is a very rare event but occasionally seen in hypercoagulable states. We present a case of a 31-year-old woman at 38 weeks of gestation who developed a severe upper abdominal pain ...and unilateral adrenal infarction due to thrombosis of the adrenal vein. The only thrombogenic factor found was pregnancy. The case highlights that adrenal infarction may complicate a normal pregnancy and should be included in the differential diagnosis of the acute abdomen in pregnancy.
Shoulder dystocia is a severe obstetric emergency that can cause substantial neonatal and maternal complications. This study aims to assess the performed obstetric maneuvers and their frequency, ...success, and association with maternal and neonatal complication rates.
The study population was collected among all deliveries in the Hospital District of Helsinki and Uusimaa between 2006 and 2015 (n = 181 352) by searching for ICD-10 codes for shoulder dystocia, brachial plexus injury and clavicle fracture. Shoulder dystocia cases (n = 537) were identified by reviewing the medical records. Shoulder dystocia cases treated with one or two maneuvers were compared with those treated with at least three. Medical records of a matched control group constituting of 566 parturients without any of the forementioned ICD-10 codes were also scrutinized.
Using the four most common obstetric maneuvers (McRoberts maneuver, suprapubic pressure, rotational maneuvers, the delivery of the posterior arm) significantly increased during the study period with individual success rates of 61.0%, 71.9%, 68.1% and 84.8%, respectively. Concurrently, the rate of brachial plexus injury and combined neonatal morbidity significantly declined from 50% to 24.2% (p = 0.02) and from 91.4% to 48.5% (p < 0.001). Approximately 75% of shoulder dystocia cases treated with maneuvers were resolved by the McRoberts maneuver and/or suprapubic pressure, but each of the four most performed maneuvers significantly increased the cumulative success rate individually and statistically (p < 0.001). The rates of brachial plexus injury and combined neonatal morbidity were at their highest (52.9% and 97.8%) when none of the maneuvers were performed and at their lowest when two maneuvers were performed (43.0% and 65.4%). The increasing number (≥3) of maneuvers did not affect the combined maternal or neonatal morbidity or brachial plexus injury but increased the risk for third- or fourth-degree lacerations (odds ratio 2.91, 95% confidence interval 1.17 to 7.24).
The increased use of obstetric maneuvers during the study period was associated with decreasing rates of neonatal complications; conversely, the lack of obstetric maneuvers was associated with the highest rate of neonatal complications. These emphasize the importance of education, maneuver training and urgently performing shoulder dystocia maneuvers according to the international protocol guidelines.
We have established estrogen-independent and antiestrogen-resistant cell lines from hormone-dependent MCF-7 breast cancer cells by long-term culture in the absence of estrogen, or in the presence of ...antiestrogen toremifene, respectively. By using a cDNA microarray we compared gene expression profiles among estrogen-independent, antiestrogen-resistant and long-term estrogen-treated MCF-7 cells. We also determined how the expression of the differentially expressed genes has developed during the long-term culture of the cell lines. Of the screened 1176 cancer-related genes, FOSL1, TIMP1, L1CAM, GDF15, and MYBL2 were found to be differentially expressed between the cell lines. A change in FOSL1 and TIMP1 expression could be attributed to the development of antiestrogen resistance, whereas induced L1CAM expression was implicated in the development of estrogen-independent growth of the cells. Estrogen regulated genes GDF15 and L1CAM became regulated by toremifene in the later passage number of toremifene-resistant cells, which might be an indication of the developed estrogen-agonistic activity of toremifene in these cells. Our findings suggest a pattern where the hormone-responsive cancer cells, which survive E2 deprivation and/or antiestrogen treatment, first acquire necessary changes in gene expression for transition to maximal growth in the new hormonal environment. Then, after prolonged treatment with antiestrogen, the antiestrogen-resistant cells may eventually generate an E2-agonistic response to antiestrogen, probably acquiring additional growth advantage.
Purpose
Shoulder dystocia is an obstetric emergency with severe complications. Our objective was to evaluate the major pitfalls in the diagnostics of shoulder dystocia, diagnostic descriptions ...documented in medical records, use of obstetric maneuvers, and their correlations to Erb’s and Klumpke’s palsy and the use of ICD-10 code 066.0.
Methods
A retrospective, register-based case–control study included all deliveries (
n
= 181 352) in Hospital District of Helsinki and Uusimaa (HUS) area in 2006–2015. Potential shoulder dystocia cases (
n
= 1708) were identified from the Finnish Medical Birth Register and the Hospital Discharge Register using ICD-10 codes O66.0, P13.4, P14.0, and P14.1. After thorough assessment of all medical records, 537 shoulder dystocia cases were confirmed. Control group consisted of 566 women without any of these ICD-10 codes.
Results
The pitfalls in the diagnostic included suboptimal following of guidelines for making the diagnosis of shoulder dystocia, subjective interpretation of diagnostic criteria, and inexact or inadequate documentation in medical records. The diagnostic descriptions in medical record were highly inconsistent. The use of obstetric maneuvers was suboptimal among shoulder dystocia cases (57.5%). Overall, the use of obstetric maneuvers increased during the study period (from 25.7 to 97.0%,
p
< 0.001), which was associated with decreasing rate of Erb’s palsy and increasing use of ICD-10 code O66.0.
Conclusion
There are diagnostic pitfalls, which could be addressed by education regarding shoulder dystocia guidelines, by improved use obstetric maneuvers, and more precise documentation. The increased use of obstetric maneuvers was associated with lower rates of Erb’s palsy and improved coding of shoulder dystocia.
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