Endometriosis is a gynaecological condition characterised by immune cell infiltration and distinct inflammatory signatures found in the peritoneal cavity. In this study, we aim to characterise the ...immune microenvironment in samples isolated from the peritoneal cavity in patients with endometriosis.
We applied mass cytometry (CyTOF), a recently developed multiparameter single-cell technique, in order to characterise and quantify the immune cells found in peritoneal fluid and peripheral blood from endometriosis and control patients.
Our results demonstrate the presence of more than 40 different distinct immune cell types within the peritoneal cavity. This suggests that there is a complex and highly heterogeneous inflammatory microenvironment underpinning the pathology of endometriosis. Stratification by clinical disease stages reveals a dynamic spectrum of cell signatures suggesting that adaptations in the inflammatory system occur due to the severity of the disease. Notably, among the inflammatory microenvironment in peritoneal fluid (PF), the presence of CD69
T cell subsets is increased in endometriosis when compared to control patient samples. On these CD69
cells, the expression of markers associated with T cell function are reduced in PF samples compared to blood. Comparisons between CD69
and CD69
populations reveal distinct phenotypes across peritoneal T cell lineages. Taken together, our results suggest that both the innate and the adaptive immune system play roles in endometriosis.
This study provides a systematic characterisation of the specific immune environment in the peritoneal cavity and identifies cell immune signatures associated with endometriosis. Overall, our results provide novel insights into the specific cell phenotypes governing inflammation in patients with endometriosis. This prospective study offers a useful resource for understanding disease pathology and opportunities for identifying therapeutic targets.
An association between BRCA pathogenic variants and an increased endometrial cancer risk, specifically serous-like endometrial cancer, has been postulated but remains unproven, particularly for BRCA2 ...carriers. Mechanistic evidence is lacking, and any link may be related to tamoxifen exposure or testing bias. Hysterectomy during risk-reducing bilateral salpingo-oophorectomy is, therefore, of uncertain benefit. Data from a large, prospective cohort will be informative.
Data on UK BRCA pathogenic variant carriers were interrogated for endometrial cancer diagnoses. Standardised incidence ratios (SIRs) were calculated in four distinct cohorts using national endometrial cancer rates; either from 1/1/1980 or age 20, prospectively from date of personal pathogenic variant report, date of family pathogenic variant report or date of risk-reducing salpingo-oophorectomy. Somatic BRCA sequencing of 15 serous endometrial cancers was performed to detect pathogenic variants.
Fourteen cases of endometrial cancer were identified in 2609 women (1350 BRCA1 and 1259 BRCA2), of which two were prospectively diagnosed. No significant increase in either overall or serous-like endometrial cancer risk was identified in any of the cohorts examined (SIR = 1.70, 95% confidence interval = 0.74–3.33; no cases of serous endometrial cancer diagnosed). Results were unaffected by the BRCA gene affected, previous breast cancer or tamoxifen use. No BRCA pathogenic variants were detected in any of the serous endometrial cancers tested.
Women with a BRCA pathogenic variant do not appear to have a significant increased risk of all-type or serous-like endometrial cancer compared with the general population. These data provide some reassurance that hysterectomy is unlikely to be of significant benefit if performed solely as a preventive measure.
•Endometrial cancer risk was not increased in BRCA1/2 pathogenic variant carriers.•Results were unaffected by BRCA gene, previous breast cancer or tamoxifen use.•No specific increase in serous-like endometrial cancer risk was identified.•Sequencing of 15 serous endometrial tumours revealed no pathogenic BRCA1/2 variants.
Endometriosis is a common gynaecological disease of women in reproductive age, and is thought to arise from retrograde menstruation and implantation of endometrial tissue, mostly into the peritoneal ...cavity. The condition is characterized by a chronic, unresolved inflammatory process thereby contributing to pain as cardinal symptom in endometriosis. Elevated reactive oxygen species (ROS) and oxidative stress have been postulated as factors in endometriosis pathogenesis. We here set out for a systematic study to identify novel mechanisms and pathways relating to oxidative stress in ectopic peritoneal lesions. Using combined proteomic and transcriptomic approaches, we identified novel targets including upregulated pro-oxidative enzymes, such as amine oxidase 3/vascular adhesion protein 1 (AOC3/VAP1) as well as downregulated protective factors, in particular alkenal reductase PTGR1 and methionine sulfoxide reductase. Consistent with an altered ROS landscape, we observed hemoglobin / iron overload, ROS production and lipid peroxidation in ectopic lesions. ROS-derived 4-hydroxy-2-nonenal induced interleukin IL-8 release from monocytes. Notably, AOC3 inhibitors provoked analgesic effects in inflammatory pain models in vivo, suggesting potential translational applicability.
To detect novel endometrial cancer risk variants, we leveraged information from endometrial cancer risk factors in a multi-trait GWAS analysis. We first assessed causal relationships between ...established and suspected endometrial cancer risk factors, and endometrial cancer using Mendelian randomization. Following multivariable analysis, five independent risk factors (waist circumference, testosterone levels, sex hormone binding globulin levels, age at menarche, and age at natural menopause) were included in a multi-trait Bayesian GWAS analysis. We identified three potentially novel loci that associate with endometrial cancer risk, one of which (7q22.1) replicated in an independent endometrial cancer GWAS dataset and was genome-wide significant in a meta-analysis. This locus may affect endometrial cancer risk through altered testosterone levels. Consistent with this, we observed colocalization between the signals for endometrial cancer risk and expression of CYP3A7, a gene involved in testosterone metabolism. Thus, our findings suggest opportunities for hormone therapy to prevent or treat endometrial cancer.
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•5 independent endometrial cancer risk factors detected via multivariable analysis•3 potentially novel endometrial cancer risk loci revealed by multi-trait GWAS•Validation of novel 7q22.1 risk locus in an endometrial cancer GWAS replication set•GWAS variants at 7q22.1 linked to CYP3A7 expression and female testosterone levels
Bioinformatics; Systems biology; Cancer; Genomics
Background
Genetic variants are considered to have a crucial impact on the occurrence of ischemic stroke. In clinical routine, the diagnostic value of next-generation sequencing (NGS) in the medical ...clarification of acute juvenile stroke has not been investigated so far.
Material and methods
We analyzed an exome-based gene panel of 349 genes in 172 clinically well-characterized patients with magnetic resonance imaging (MRI)-proven, juvenile (age ≤ 55 years), ischemic stroke admitted to a single comprehensive stroke center.
Results
Monogenetic diseases causing ischemic stroke were observed in five patients (2.9%): In three patients with lacunar stroke (1.7%), we identified pathogenic variants in
NOTCH3
causing cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Hence, CADASIL was identified at a frequency of 12.5% in the lacunar stroke subgroup. Further, in two male patients (1.2%) suffering from lacunar and cardioembolic stroke, pathogenic variants in
GLA
causing Fabry’s disease were present. Additionally, genetic variants in monogenetic diseases lacking impact on stroke occurrence, variants of unclear significance (VUS) in monogenetic diseases, and (cardiovascular-) risk genes in ischemic stroke were observed in a total of 15 patients (15.7%).
Conclusion
Genetic screening for Fabry’s disease in cardioembolic and lacunar stroke as well as CADASIL in lacunar stroke might be beneficial in routine medical work-up of acute juvenile ischemic stroke.
Background:Rates of endometrial cancer incidence and mortality are rising as a result of increasing rate of obesity and an aging population. Diagnosed early, endometrial cancer has an excellent ...prognosis but those with advanced disease have a very poor outlook. Epidemiological risk factors fail to accurately stratify women and there is no standardised screening programme for endometrial cancer. A growing body of evidence suggests that genetic factors contribute to the risk. The aim of this project was to investigate the potential benefit of genomic tools for predicting the risk of endometrial cancer to enable targeted and personalised prevention.Methods: i) A systematic review of the literature was performed to identify a panel of robust single nucleotide polymorphisms (SNPs) contributing to endometrial cancer risk. ii) A genome-wide association study (GWAS) was conducted in a case-control study from the North West of England to identify and validate SNPs associated with endometrial cancer. iii) A polygenic risk score (PRS) was developed and refined in this cohort followed by validation in additional datasets. iv) The relationship between endometrial cancer risk and pathogenic BRCA variants was investigated by comparing the prevalence of cases identified in a BRCAcarrier database to the general population. DNA sequencing was undertaken to examine the presence of any somatic pathogenic mutations.Results:24 SNPs most likely to influence endometrial cancer risk were identified through the systematic review. Six risk regions of suggestive significance were identified in the Manchester GWAS. 72 externally curated SNPs were investigated where a significant association was confirmed for ten SNPs. A refined PRS consisting of 40 SNPs was developed in our independent cohort resulting in 62% discriminatory ability. The PRS was applied to two other datasets with low to moderate success. No evidence for an increased risk of endometrial cancer in BRCA pathogenic carriers was observed. No pathogenic BRCA somatic mutations were identified in serous subtype tumours.Conclusions: In this project, we report strong evidence in favour of SNPs influencing endometrial cancer risk and have independently validated the most robust SNPs. A PRS based on the most predictive SNPs was moderately capable of risk stratification at a level similar to published multivariable risk prediction models. If successfully validated, the PRS may be useful in improving the accuracy of risk prediction models in risk-based care. Risk-reduction measures and incorporation into risk prediction models are not warranted for carriers of pathogenic BRCAmutations.
Increased adiposity is a known risk factor for endometrial cancer (EC). This study aimed to disentangle the separate causal roles of child and adult adiposity on EC risk in adults, including ...endometrioid and non-endometrioid histological subtypes using multivariable Mendelian randomisation. These analyses employed genetic associations derived from UK Biobank as proxies for child and adult body size in 12,906 cases and 108,979 controls that participated in the Endometrial Cancer Association Consortium. In multivariable analyses, adult body size increased overall EC (OR 2.30, 95% CI 1.73-3.06) and endometrioid EC risk (OR 2.28, 95% CI 1.65-3.16), while child body size had minimal effect. In contrast, child body size (OR 2.26, 95% CI 1.03-4.99) but not adult body size increased non-endometrioid EC risk. As such, child adiposity has an indirect effect on endometrioid EC risk that is mediated by adult adiposity but has a direct effect on non-endometrioid EC risk that is independent of adult adiposity. These novel findings indicate that interventions targeting adiposity during distinct periods in life have a critical role in preventing subtype-specific EC.
The minor allele of the genetic variant rs10191329 in the DYSF‐ZNF638 locus is associated with unfavorable long‐term clinical outcomes in multiple sclerosis patients. We investigated if rs10191329 is ...associated with brain atrophy measured by magnetic resonance imaging in a discovery cohort of 748 and a replication cohort of 360 people with relapsing multiple sclerosis. We observed an association with 28% more brain atrophy per rs10191329*A allele. Our results encourage stratification for rs10191329 in clinical trials. Unraveling the underlying mechanisms may enhance our understanding of pathophysiology and identify treatment targets. ANN NEUROL 2023;94:1080–1085
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