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Single-nucleotide variations (SNVs) (formerly single-nucleotide polymorphism [SNV]) influence genetic predisposition to endometrial cancer. We hypothesized that a polygenic risk score (PRS) comprising multiple SNVs may improve endometrial cancer risk prediction for targeted screening and prevention.We developed PRSs from SNVs identified from a systematic review of published studies and suggestive SNVs from the Endometrial Cancer Association Consortium. These were tested in an independent study of 555 surgically-confirmed endometrial cancer cases and 1202 geographically-matched controls from Manchester, United Kingdom and validated in 1676 cases and 116,960 controls from the UK Biobank (UKBB).Age and body mass index predicted endometrial cancer in both data sets (Manchester: area under the receiver operator curve [AUC] = 0.77, 95% CI = 0.74-0.80; UKBB: AUC = 0.74, 95% CI = 0.73-0.75). The AUC for PRS19, PRS24, and PRS72 were 0.58, 0.55, and 0.57 in the Manchester study and 0.56, 0.54, and 0.54 in UKBB, respectively. For PRS19, women in the third tertile had a 2.1-fold increased risk of endometrial cancer compared with those in the first tertile of the Manchester study (odds ratio = 2.08, 95% CI = 1.61-2.68, PAn endometrial cancer risk prediction model incorporating a PRS derived from multiple SNVs may help stratify women for screening and prevention strategies.

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.

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.

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.

Endometriosis is a common chronic inflammatory condition causing pelvic pain and infertility in women, with limited treatment options and 50% heritability. We leveraged genetic analyses in two species with spontaneous endometriosis, humans and the rhesus macaque, to uncover treatment targets. We sequenced DNA from 32 human families contributing to a genetic linkage signal on chromosome 7p13-15 and observed significant overrepresentation of predicted deleterious low-frequency coding variants in NPSR1, the gene encoding neuropeptide S receptor 1, in cases (predominantly stage III/IV) versus controls (P = 7.8 × 10-4). Significant linkage to the region orthologous to human 7p13-15 was replicated in a pedigree of 849 rhesus macaques (P = 0.0095). Targeted association analyses in 3194 surgically confirmed, unrelated cases and 7060 controls revealed that a common insertion/deletion variant, rs142885915, was significantly associated with stage III/IV endometriosis (P = 5.2 × 10-5; odds ratio, 1.23; 95% CI, 1.09 to 1.39). Immunohistochemistry, qRT-PCR, and flow cytometry experiments demonstrated that NPSR1 was expressed in glandular epithelium from eutopic and ectopic endometrium, and on monocytes in peritoneal fluid. The NPSR1 inhibitor SHA 68R blocked NPSR1-mediated signaling, proinflammatory TNF-α release, and monocyte chemotaxis in vitro (P < 0.01), and led to a significant reduction of inflammatory cell infiltrate and abdominal pain (P < 0.05) in a mouse model of peritoneal inflammation as well as in a mouse model of endometriosis. We conclude that the NPSR1/NPS system is a genetically validated, nonhormonal target for the treatment of endometriosis with likely increased relevance to stage III/IV disease.

We have performed genetic correlation and Mendelian randomization analyses using publicly available genome-wide association study (GWAS) data to identify endometrial cancer risk factors. These and previously established risk factors of endometrial cancer were then included in a multi-trait Bayesian GWAS analysis to detect endometrial cancer susceptibility variants, identifying three novel loci (7q22.1, 8q24.3 and 16q12.2); two of which were replicated in an independent endometrial cancer GWAS dataset. These loci are hypothesized to affect endometrial cancer risk through altered sex-hormone levels or through effects on obesity. Consistent with this hypothesis, several genes with established roles in these pathways (CYP11B1, CYP3A7, IRX3 and IRX5) were prioritized as candidate endometrial cancer risk genes by interrogation of quantitative trait loci data and chromatin capture assays in endometrial cell lines. The findings of this study identify additional opportunities for hormone treatment and further support weight loss to reduce the risk of developing endometrial cancer.Statement of SignificanceThis study prioritizes four genes related to testosterone and obesity as candidate endometrial cancer risk genes, as well as identifies additional opportunities for hormone treatment and further supports weight loss to reduce endometrial cancer risk.

Funder: national institute of health research, INTRODUCTION: Endometrial cancer is one of the most commonly diagnosed cancers in women. Although there is a hereditary component to endometrial cancer, most cases are thought to be sporadic and lifestyle related. The aim of this study was to systematically review prospective and retrospective case-control studies, meta-analyses and genome-wide association studies to identify genomic variants that may be associated with endometrial cancer risk. METHODS: We searched MEDLINE, Embase and CINAHL from 2007 to 2019 without restrictions. We followed PRISMA 2009 guidelines. The search yielded 3015 hits in total. Following duplicate exclusion, 2674 abstracts were screened and 453 full-texts evaluated based on our pre-defined screening criteria. 149 articles were eligible for inclusion. RESULTS: We found that single nucleotide polymorphisms (SNPs) in HNF1B, KLF, EIF2AK, CYP19A1, SOX4 and MYC were strongly associated with incident endometrial cancer. Nineteen variants were reported with genome-wide significance and a further five with suggestive significance. No convincing evidence was found for the widely studied MDM2 variant rs2279744. Publication bias and false discovery rates were noted throughout the literature. CONCLUSION: Endometrial cancer risk may be influenced by SNPs in genes involved in cell survival, oestrogen metabolism and transcriptional control. Larger cohorts are needed to identify more variants with genome-wide significance.

Background 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. Methods 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. Results 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. Conclusions 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., Highlights • 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.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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.

Additional file 1: Lists of antibody and patients information used in this study and additional figures in support of the mass cytometry analysis. Table S1. Related to Fig. 1 and Experimental Procedures. Details of antibodies used in this study. Table S2. Related to Fig. 1. Information of 20 patients from whom PF and blood are used in this study. Table S3. Related to Fig. 1, Fig. 2 and Fig. 6. Markers used to define immune cell types. Table S4. Related to Fig. 4 and Experimental Procedures. Antibodies used in the analysis of 38 PF samples. Table S5. Related to Fig. 4. Information of 38 patients in follow up study. Table S6. Related to Fig. 6 and Experimental Procedures. Antibodies used in the T cell panel. Table S7. Related to Fig. 6. Information of 11 patient samples used in T cell panel study. Figure S1. Graphic workflow of CyTOF study comparing PFCs and PBCs. Figure S2 and Figure S3. Related to Fig. 1, Fig. 2 and Fig. 6. Manual gating of cells subsets and functional markers. Figure S4. Related to Fig. 1. Clustering of PF and blood samples by PCA. Figure S5. Related to Fig. 1. Phenotypic mapping of PBCs. Figure S6. Related to Fig. 2. Percentage of major immune cells types in blood and PF samples and expression of functional markers. Figure S7. Related to Fig. 2. Cell counts show changes of major cell populations in PF compared to peripheral blood. Figure S8. Related to Fig. 3. Differential expression of CD69 in endometriosis was not affected by menstruation or hormone. Figure S9. Related to Fig. 4. Cell counts of major cell subtypes in PFCs at disease stages and evaluation of confounding effects from menstrual cycle and hormones. Figure S10. Related to Fig. 4. A. PCA separates endometriosis (Endo) and control in PF but not blood samples. Figure S11. Related to Fig. 6. ViSNE plot showing composition of T cells and comparison of CD69 abundance on T cell lineages between control and endometriosis samples from PF.

Endometrial cancer (EC) is the most common of gynecological cancers in the UK. There is evidence for genetic predisposition to EC, however, single nucleotide polymorphisms have not been considered in risk prediction models so far. We hypothesized that a polygenic risk score (PRS) based on a panel of robust SNPs may be useful to predict women at high risk of developing EC. We conducted a systematic review to identify the most robust SNPs which may be associated with EC risk. The resulting panel of SNPs was validated in an independent cohort comprising EC cases, and control women with intact uterus. In the present study, we used 560 cases and 1202 controls of broad-European origin to construct a PRS. Our systematic review suggested twenty four SNPs, nineteen of which were reported to reach genome-wide significance in large GWAS. Preliminary results using 560 cases and 1202 controls produced effect sizes, directions and dosages similar to published data. The mean PRS for EC cases was 0.64 (SD=0.43, 95%CI 0.60-0.68) while mean PRS for controls was 0.48 (SD=0.42, 95% CI 0.46-0.51). The AUC of the PRS achieved was 0.61. Women in the highest tertile of the PRS score had a 2.4 times increased risk of developing EC compared to women in the lowest tertile (OR=2.40, 95%CI 1.85-3.09, p = 1.47E-11). Women in the mid tertile also had a modestly increased risk of EC compared to the lowest tertile (OR=1.40, 95%CI 1.06-1.84, p = 0.017). There was a clear trend of increasing risk with category (p = 6.25E-12). There is mounting evidence for polygenic input from common variants in EC susceptibility. Our results, for the first time, validate the potential use of a PRS for risk stratification of women at high risk of EC. When considered alongside epidemiological risk factors, the PRS could provide a good discrimination for early detection and prevention of EC in a clinical setting. Citation Format: Cemsel Bafligil, Deborah J. Thompson, Artitaya Lophatananon, Miriam J. Smith, Joe Dennis, Gareth D. Evans, Emma J. Crosbie. A polygenic risk score-based genetic stratification for endometrial cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2322.

Additional file 2. Related to Fig. 1. Patient-by-patient minimum spanning tree plots showing cell clustering of PF and blood samples.

Additional file 2. Related to Fig. 1. Patient-by-patient minimum spanning tree plots showing cell clustering of PF and blood samples.