Risk Of Endometrial Cancer Research Articles

Rare germline genetic variation in PAX8 transcription factor binding sites and susceptibility to epithelial ovarian cancer.

Common genetic variation throughout the genome together with rare coding variants identified to date explain about a half of the inherited genetic component of epithelial ovarian cancer risk. It is likely that rare variation in the non-coding genome will explain some of the unexplained heritability, but identifying such variants is challenging. The primary problem is lack of statistical power to identifying individual risk variants by association as power is a function of sample size, effect size and allele frequency. Power can be increased by using burden tests which test for association of carriers of any variant in a specified genomic region. This has the effect of increasing the putative effect allele frequency. PAX8 is a transcription factor that plays a critical role in tumour progression, migration and invasion. Furthermore, regulatory elements proximal to target genes of PAX8 are enriched for common ovarian cancer risk variants. We hypothesised that rare variation in PAX8 binding sites are also associated with ovarian cancer risk, but unlikely to be associated with risk of breast, colorectal or endometrial cancer. We have used publicly available, whole-genome sequencing data from the UK 100,000 Genomes Project to evaluate the burden of rare variation in PAX8 binding sites across the genome. Data were available for 522 ovarian cancers, 2,984 breast cancers, 2,696 colorectal cancers, 836 endometrial cancers and 2253 non-cancer controls. Active binding sites were defined using data from multiple PAX8 and H3K27 ChIPseq experiments. We found no association between the burden of rare variation in PAX8 binding sites (defined in several ways) and risk of ovarian, breast or endometrial cancer. An apparent association with colorectal cancer was likely to be a technical artefact as a similar association was also detected for rare variation in random regions of the genome. Despite the null result this study provides a proof-of -principle for using burden testing to identify rare, non-coding germline genetic variation associated with disease. Larger sample sizes available from large-scale sequencing projects together with improved understanding of the function of the non-coding genome will increase the potential of similar studies in the future.

Biomolecular Classification in Endometrial Cancer: Onset, Evolution, and Further Perspectives: A Critical Review.

Since the new guidelines for endometrial cancer risk classification have been published, many reviews have proposed a critical re-evaluation. In this review, we look back to how the molecular classification system was built and its evolution in time to highlight the major flaws, particularly the biases stemming from the inherent limitations of the cohorts involved in the discoveries. A significant drawback in some cohorts is the inclusion criteria, as well as the retrospective nature and the notably sparse numbers, especially in the POLEmut (nonsynonymous mutation in EDM domain of POLE) risk groups, all of which impact the reliability of outcomes. Additionally, a disregard for variations in follow-up duration leads to a non-negligible bias, which raises a substantial concern in data interpretation and guideline applicability. Finally, according to the results that we obtained through a re-analysis of the confirmation cohort, the p53abn (IHC positive for p53 protein) subgroup, which is predominant in non-endometrioid histology (73-80%), loses its predictivity power in the endometrioid cohort of patients. The exclusion of non-endometrioid subtypes from the cohort led to a complete overlap of three molecular subgroups (all except POLEmut) for both overall and progression-free survival outcomes, suggesting the need for a more histotype-specific approach. In conclusion, this review challenges the current ESGO/ESTRO/ESP guidelines on endometrial cancer risk classification and highlights the limitations that must be addressed to better guide the clinical decision-making process.

Endometrial cancer risk stratification using MRI radiomics: corroborating with choline metabolism

Background and purposeRadiomics offers little explainability. This study aims to develop a radiomics model (Rad-Score) using diffusion-weighted imaging (DWI) to predict high-risk patients for nodal metastasis or recurrence in endometrial cancer (EC) and corroborate with choline metabolism.Materials and methodsFrom August 2015 to July 2018, 356 EC patients were enrolled. Rad-Score was developed using LASSO regression in a training cohort (n = 287) and validated in an independent test cohort (n = 69). MR spectroscopy (MRS) was also used in 230 patients. Nuclear MRS measured choline metabolites in 70 tissue samples. The performance was compared against European Society for Medical Oncology (ESMO) risk groups. A P < .05 denoted statistical significance.ResultsRad-Score achieved 71.1% accuracy in the training and 71.0% in the testing cohorts. Incorporating clinical parameters of age, tumor type, size, and grade, Rad-Signature reached accuracies of 73.2% in training and 75.4% in testing cohorts, closely matching the performance to the post-operatively based ESMO's 70.7% and 78.3%. Rad-Score was significantly associated with increased total choline levels on MRS (P = .034) and tissue levels (P = .019).ConclusionsDevelopment of a preoperative radiomics risk score, comparable to ESMO clinical standard and associated with altered choline metabolism, shows translational relevance for radiomics in high-risk EC patients.Trial registrationThis study was registered in ClinicalTrials.gov on 2015–08-01 with Identifier NCT02528864.

Deep learning model utilizing fluorescence lifetime imaging microscopy and confidence learning for predicting endometrial cancer risk

This study introduces a novel diagnostic approach for the prediction of endometrial cancer risk, which involves minimally invasive exfoliation cytology specimens from 63 participants, staining with the viscosity-sensitive fluorescent probe DCVJ, and detection by fluorescence lifetime imaging microscopy (FLIM). Initially, DCVJ-stained tissue sections from cancerous and normal regions were utilized to confirm the elevated viscosity in cancerous lesions. Subsequently, DCVJ-stained aspirated cell samples were detected by FLIM to capture viscosity characteristics and cellular morphology. A total of 2348 FLIM images collected from 42 individuals, were utilized for training purposes. A deep learning model, incorporating confidence learning, was developed and demonstrated a sensitivity of 84.6% and specificity of 75.0% in predicting endometrial cancer risk. This study highlights the potential of the deep learning-FLIM model for the prediction of endometrial cancer risk.

Polymorphisms in miR-17-92 cluster promoter region is associated with risk and prognosis of endometrial cancer.

Accumulating researches have reported that miR-17-92 cluster expression has strong association with tumorigenesis. In this study, we investigated the effects of 2 genetic polymorphisms in the promoter region of the miR-17-92 cluster and the risk and prognosis of endometrial cancer in northern Chinese women. Two polymorphisms (rs9588884 and rs982873) in the promoter of miR-17-92 cluster were genotyped by polymerase chain reaction and ligase detection reaction (PCR-LDR) in398 EC patients and 420 controls. The levels of miR-17-92 mRNA were investigated in 65EC tissues by real-time quantitative polymerase chain reaction (RT-qPCR). The impact of genetic features on the risk and clinical outcomes of EC was analyzed. The prognostic value of hsa-miR-17 and hsa-miR-20a in EC patients was assessed using the Kaplan-Meier plotter database. The results showed that a significant decrease in risk of EC with rs9588884 (GG vs CC: OR = 0.49, 95% CI = 0.32-0.78, P = .002; G vs C: OR = 0.75, 95% CI = 0.62-0.91, P = .005, respectively). Similarly, association was found between rs982873 and a decreased risk of EC (CC vs TT: OR = 0.53, 95% CI = 0.34-0.82, P = .004; C vs T: OR = 0.77, 95% CI = 0.63-0.94, P = .010, respectively). Moreover, survival analysis showed that the CG or GG genotype of rs9588884 may significantly increase overall survival (OS) compared with the CC genotype in the 5-year follow-up (HR = 0.49, 95% CI = 0.29-0.82 and HR = 0.36, 95% CI = 0.16-0.83, respectively). RT-qPCR results showed that the expression level of miR-17-92 mRNA in EC tissues with the rs9588884 GG genotype was significantly lower than those with the GC + CC genotype (P = .030). However, there was no significant difference in the prognosis and expression level of miR-17-92mRNA in tissues of EC patients with different genotypes of rs982873 (P = .343). In addition, analysis using Kaplan-Meier plotter database showed that high hsa-miR-20a expression was significantly correlated with poor OS in EC patients (HR = 1.63, 95% CI = 1.02-2.61, P = .039). The genetic polymorphisms rs9588884 and rs982873 in the promoter of miR-17-92 cluster decreased EC risk. Both rs9588884 and the expression level of hsa-miR-20a mRNA may be associated with its clinical outcome in EC patients.

Pre-receptor regulation of 11-oxyandrogens differs between normal and cancerous endometrium and across endometrial cancer grades and molecular subtypes.

Endometrial cancer (EC) is a prevalent gynecological malignancy globally, with a rising incidence trend. While classic androgens have been implicated with EC risk, the role of their 11-oxygenated metabolites is poorly understood. Here, we studied 11-oxyandrogen formation from steroid precursors in EC for the first time. We performed in vitro studies on a panel of four EC cell lines of varying differentiation degree and molecular subtype and a control cell line of normal endometrium to assess 11-oxyandrogen formation from steroid precursors. We also characterized the transcriptomic effects of dihydrotestosterone (DHT) and 11-keto-DHT on Ishikawa and RL95-2. Key molecular players in 11-oxyandrogen metabolism and action were explored in endometrial tumors using public transcriptomic datasets. We discovered that within endometrial tumors, the formation of 11-oxyandrogens does not occur from classic androgen precursors. However, we observed distinct regulatory mechanisms at a pre-receptor level in normal endometrium compared to cancerous tissue, and between low- and high-grade tumors. Specifically, in vitro models of low-grade EC formed higher levels of bioactive 11-keto-testosterone from 11-oxyandrogen precursors compared to models of noncancerous endometrium and high-grade, TP53-mutated EC. Moreover, the potent androgen, DHT and its 11-keto homologue induced mild transcriptomic effects on androgen receptor (AR)-expressing EC model, Ishikawa. Finally, using public transcriptomic datasets, we found HSD11B2 and SRD5A2, coding for key enzymes in steroid metabolism, to be associated with better disease-specific survival, whereas higher intra-tumoral AR expression correlated with lower recurrence in TP53-wt tumors. The intra-tumoral metabolism of 11-oxyandrogen precursors is characteristic for low-grade EC of non-TP53-alt molecular subtypes. Our findings support further exploration of circulating 11-oxyandrogens as prognostic biomarkers in EC.

Association between the non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) and risk of endometrial cancer among US adults: A population-based study.

123 Background: Endometrial cancer, as one of the metabolic-related malignancies, is becoming a significant public health concern worldwide. The non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) has emerged as a comprehensive biomarker of various lipid-related metabolic disorders. However, the association of NHHR with endometrial cancer risk remains unclear to date. Therefore, we conducted this nationwide cross-sectional study to investigate the association of NHHR with the risk of endometrial cancer among US adults. Methods: Data were obtained from the National Health and Nutrition Examination Survey (1999–2018). Female participants who provided complete data on the NHHR and endometrial cancer were enrolled. The association of the NHHR with endometrial cancer was assessed by multivariate logistic regression analyses, adjusted by multiple potential confounders. Meanwhile, sensitivity analyses and subgroup analyses were conducted. Results: A total of 25,411 eligible participants were enrolled, including 214 (0.8%) women with endometrial cancer. The fully-adjusted multivariate logistic model showed a significantly positive association of NHHR with the endometrial cancer risk (odds ratio [OR] 1.15, 95% confidence interval [CI]: 1.05–1.25; P=0.003). Comparing the highest to the lowest quartile of NHHR, the fully-adjusted OR was 1.52 (95% CI: 1.02–2.28, P for trend=0.017). In subgroup analyses, the significantly positive association between NHHR and the risk of endometrial cancer was also found in non-obese women (OR 1.18, 95% CI: 1.04–1.35, P=0.012), women without diabetes (OR 1.15, 95% CI: 1.02–1.30, P=0.027), women with hypertension (OR 1.15, 95% CI: 1.03–1.28, P=0.012), women who use oral contraceptives (OR 1.16, 95% CI: 1.04–1.30, P=0.009) and in parous women(OR 1.15, 95% CI: 1.05–1.27, P=0.003). Additionally, in the sensitivity analysis by excluding participants with NHHR below 5% or above 95% in total cohort, the positive association of NHHR with endometrial cancer risk remained significant (OR 1.21, 95% CI: 1.03–1.42, P=0.018). Conclusions: This population-based study found that a higher NHHR correlated with an increased risk of endometrial cancer among the US population. Our findings suggested that NHHR might be a promising tool for the risk assessment of endometrial cancer. Prospective studies are necessary to further verify these findings. [Table: see text]

Hepatitis B virus infection and the risk of gynecologic cancers: a systematic review and meta-analysis

ObjectivesThe relationship between hepatitis B virus (HBV) infection and gynecologic cancers is controversial. We aimed to evaluate the risk of gynecologic cancers associated with HBV infection using a meta-analysis.MethodsTwo independent reviewers identified publications in the PubMed, Embase and Cochrane Library databases that reported an association between HBV and the risk of gynecologic malignancy from inception to December 31, 2022. The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of the included articles. Pooled odds ratios (ORs) and 95% corresponding confidence intervals (CIs) were calculated using a fixed effects model or random effects model.ResultsWe collected data from 7 studies that met the inclusion criteria, including 2 cohort studies and 5 case-control studies. HBV was significantly associated with the risk of cervical cancer in the general population (OR 1.22, 95% CI 1.09–1.38, P = 0.001), although the same trend was not found in endometrial cancer (OR 1.30, 95% CI 0.95–1.77, P = 0.105) and ovarian cancer (OR 1.03, 95% CI 0.79–1.35, P = 0.813). Subgroup analysis showed that HBV infection was positively associated with the risk of cervical cancer (OR 1.27, 95% CI 1.13–1.44, P = 0.000) in case-control studies. Asian women infected with HBV have a significantly increased risk of cervical cancer (OR 1.24, 95% CI 1.10–1.40, P = 0.001) and endometrial cancer (OR 1.46, 95% CI 1.07–1.99, P = 0.018). Hospital-based studies were found to be associated with an increased risk of cervical cancer (OR 1.30, 95% CI 1.14–1.47, P = 0.000) and endometrial cancer (OR 1.61, 95% CI 1.04–2.49, P = 0.032). The results of Begg’s and Egger’s tests showed no publication bias.ConclusionsThis meta-analysis shows a positive association between HBV infection and cervical cancer. HBV is positively correlated with the risk of cervical cancer and endometrial cancer in Asian women and hospital-based populations. More multicenter prospective studies are required to confirm the findings.

Economic Burden of Endometrial Cancer Associated With Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among reproductive-aged females, and women with PCOS are at increased risk for endometrial cancer (EndoCA), the most common gynecological malignancy. Our study sought to assess the economic burden associated with EndoCA in PCOS. Using PRISMA systematic review guidelines, we evaluated studies on EndoCA rates in patients with PCOS. Excluded studies were reviews and case reports, non-human subjects, without controls, without full text available, or reporting solely on other conditions. Selected studies were assessed for quality using the Newcastle-Ottawa Scale (NOS). Meta-analysis used DerSimonian-Laird random effects model to assess pooled risk ratio (RR). Excess cost was assessed in U.S. dollars (USD). Of 98 studies screened, nine were included. Pooled RR for EndoCA in PCOS was 3.46 (95% CI 2.28-5.23), p=<0.001. In the US, prevalence of EndoCA in patients with PCOS in 2020 was 1.712%, compared with a baseline estimated prevalence in all women of 0.489%. The excess prevalence of EndoCA attributable to PCOS was 1.223%, approximately 98,348 affected women. A population-attributable fraction of EndoCA for PCOS was 24.4%. Given estimated cost of EndoCA exceeds $1.9 billion (in 2023 USD), the economic burden of EndoCA attributable to PCOS exceeds $467 million/year. The excess annual healthcare cost for EndoCA attributable to PCOS exceeds $467 million/year (2023 USD) for the US. Although a concerning morbidity of PCOS, it is notable that the economic burden of EndoCA attributable to the disorder represents only a small fraction of its total healthcare burden.

Gynaecological cancer surveillance for women with Lynch syndrome: systematic review and cost-effectiveness evaluation.

Lynch syndrome is an inherited condition which leads to an increased risk of colorectal, endometrial and ovarian cancer. Risk-reducing surgery is generally recommended to manage the risk of gynaecological cancer once childbearing is completed. The value of gynaecological colonoscopic surveillance as an interim measure or instead of risk-reducing surgery is uncertain. We aimed to determine whether gynaecological surveillance was effective and cost-effective in Lynch syndrome. We conducted systematic reviews of the effectiveness and cost-effectiveness of gynaecological cancer surveillance in Lynch syndrome, as well as a systematic review of health utility values relating to cancer and gynaecological risk reduction. Study identification included bibliographic database searching and citation chasing (searches updated 3 August 2021). Screening and assessment of eligibility for inclusion were conducted by independent researchers. Outcomes were prespecified and were informed by clinical experts and patient involvement. Data extraction and quality appraisal were conducted and results were synthesised narratively. We also developed a whole-disease economic model for Lynch syndrome using discrete event simulation methodology, including natural history components for colorectal, endometrial and ovarian cancer, and we used this model to conduct a cost-utility analysis of gynaecological risk management strategies, including surveillance, risk-reducing surgery and doing nothing. We found 30 studies in the review of clinical effectiveness, of which 20 were non-comparative (single-arm) studies. There were no high-quality studies providing precise outcome estimates at low risk of bias. There is some evidence that mortality rate is higher for surveillance than for risk-reducing surgery but mortality is also higher for no surveillance than for surveillance. Some asymptomatic cancers were detected through surveillance but some cancers were also missed. There was a wide range of pain experiences, including some individuals feeling no pain and some feeling severe pain. The use of pain relief (e.g. ibuprofen) was common, and some women underwent general anaesthetic for surveillance. Existing economic evaluations clearly found that risk-reducing surgery leads to the best lifetime health (measured using quality-adjusted life-years) and is cost-effective, while surveillance is not cost-effective in comparison. Our economic evaluation found that a strategy of surveillance alone or offering surveillance and risk-reducing surgery was cost-effective, except for path_PMS2 Lynch syndrome. Offering only risk-reducing surgery was less effective than offering surveillance with or without surgery. Firm conclusions about clinical effectiveness could not be reached because of the lack of high-quality research. We did not assume that women would immediately take up risk-reducing surgery if offered, and it is possible that risk-reducing surgery would be more effective and cost-effective if it was taken up when offered. There is insufficient evidence to recommend for or against gynaecological cancer surveillance in Lynch syndrome on clinical grounds, but modelling suggests that surveillance could be cost-effective. Further research is needed but it must be rigorously designed and well reported to be of benefit. This study is registered as PROSPERO CRD42020171098. This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR129713) and is published in full in Health Technology Assessment; Vol. 28, No. 41. See the NIHR Funding and Awards website for further award information.

Public awareness and provider counseling regarding postmenopausal bleeding as a symptom of endometrial cancer.

Our study aims to understand public knowledge of postmenopausal bleeding as an endometrial cancer symptom and how past provider counseling on postmenopausal bleeding affects knowledge and care-seeking behaviors related to postmenopausal bleeding. This was a cross-sectional survey study of people assigned female at birth. Study participants were recruited at a university research facility located at the Minnesota State Fair in September 2021. Participants answered questions about demographics, endometrial cancer knowledge, whether they had received counseling about postmenopausal bleeding, and whether and when they would present for care after experiencing postmenopausal bleeding. Six hundred forty-eight surveys were completed and included in analyses. Sixty-three percent of participants identified postmenopausal bleeding as a symptom of endometrial cancer. Those who correctly selected this symptom were more likely to be born in the United States, have a college education or higher, and have private insurance. Of the 145 postmenopausal participants, 46.5% reported that their provider counseled them on postmenopausal bleeding. Fifty-nine percent of the postmenopausal participants reported that they would tell their provider if they had postmenopausal bleeding after only one episode. There is a need for increased recognition of postmenopausal bleeding and provider counseling on postmenopausal bleeding, and educational interventions should focus on public and provider awareness of endometrial cancer risks and symptoms.

Molecular Regulator Driving Endometriosis Towards Endometrial Cancer: A Multi-Scale Computational Investigation to Repurpose Anti-Cancer drugs.

Endometriosis is a gynecological disorder among reproductive-aged women. Recent epidemiological investigations suggest endometriosis increases the risk of endometrial cancer. However, the molecular entity leading to endometriosis-to-endometrial cancer is largely unknown. This study aimed to combine a variety of computational approaches to identify the key therapeutic target promoting endometriosis-to-endometrial cancer and screen potential inhibitors against target to prevent cancer development. Our systematic investigations, includes transcriptomic profiling, protein network, pharmacophore modeling, docking, binding free energy calculation, dynamics simulation, and quantum mechanics. The gene expression analysis on endometriosis and endometrial cancer was performed and showed 108 shared upregulated genes in both conditions. Further construction of interaction network with 108 genes showed intercellular adhesion molecule 1 (ICAM1) to be a crucial molecule with a high degree of connectivity that influences vital mechanisms related to cancer pathways. We then generated ligand-based pharmacophore models using established ICAM1 inhibitors. Among the models, the ADRRR_8 pharmacophore exhibited a robust area under curve (AUC = 0.83), was employed to screen 1739 anti-cancer drugs. On screening, 421 anti-cancer drugs displayed ICAM1-inhibiting pharmacophore features. Further, the docking of 421 drugs with ICAM1 showed lanreotide (-7.80 kcal/mol) with better affinity than the reference ICAM1 inhibitor (-3.59 kcal/mol). Further validation though binding free energy and dynamics simulation of the lanreotide-ICAM1 complex showed a high binding affinity of -55.90 kcal/mol and contributed stable confirmation. According to quantum chemical calculations, lanreotide's electronic properties favour ICAM1 binding with highest occupied molecular orbital was -6.91 eV and lowest unoccupied molecular orbital was -3.93 eV. Our study supports using lanreotide to treat endometriosis, which could delay or prevent endometrial cancer. These predictions need to be confirmed and examined to determine the use of lanreotide in endometriosis treatment.

Modern view of the problem: the influence of obesity as a key component of metabolic syndrome on the development and progression of endometrial cancer

Unlike many other malignancies, the incidence and mortality of endometrial cancer continues to rise. This unfortunate trend is in no small part the result of the worldwide obesity epidemic, which is caused by reduced physical activity, poor diet and chronic stress. Currently, more than 50 % of endometrial cancer cases are associated with obesity, which is recognized as an independent risk factor for the development of this disease. Adipose tissue is not only the main place of storage of excess energy, but also a full-fledged endocrine organ that affects the metabolism, immune response and production of biologically active substances involved in cell growth and differentiation, angiogenesis, apoptosis and carcinogenesis. In this review, we assess the impact of obesity as a key component of metabolic syndrome on the development and progression of endometrial cancer. There are several mechanisms by which obesity enlarges the risk of endometrial cancer, including increased endogenous sex steroid hormones, hyperglycemia, insulin resistance, adipokine secretion, and chronic inflammation. The purpose of this review is to analyze publications, reflecting the already known aspects of the biological effect of obesity, as well as new data from recent years.

Using Genetics to Investigate Relationships between Phenotypes: Application to Endometrial Cancer.

Genome-wide association studies (GWAS) have accelerated the exploration of genotype-phenotype associations, facilitating the discovery of replicable genetic markers associated with specific traits or complex diseases. This narrative review explores the statistical methodologies developed using GWAS data to investigate relationships between various phenotypes, focusing on endometrial cancer, the most prevalent gynecological malignancy in developed nations. Advancements in analytical techniques such as genetic correlation, colocalization, cross-trait locus identification, and causal inference analyses have enabled deeper exploration of associations between different phenotypes, enhancing statistical power to uncover novel genetic risk regions. These analyses have unveiled shared genetic associations between endometrial cancer and many phenotypes, enabling identification of novel endometrial cancer risk loci and furthering our understanding of risk factors and biological processes underlying this disease. The current status of research in endometrial cancer is robust; however, this review demonstrates that further opportunities exist in statistical genetics that hold promise for advancing the understanding of endometrial cancer and other complex diseases.

Insights into inflammation and implications for the pathogenesis and long-term outcomes of endometrial cancer: genome-wide surveys and a clinical cohort study

BackgroundDespite evidence showing a connection between inflammation and endometrial cancer (EC) risk, the surveys on genetic correlation and cohort studies investigating the impact on long-term outcomes have yet to be refined. We aimed to address the impact of inflammation factors on the pathogenesis, progression and consequences of EC.MethodsFor the genetic correlation analyses, a two-sample of Mendelian randomization (MR) study was applied to investigate inflammation-related single-nucleotide polymorphisms involved with endometrial cancer from GWAS databases. The observational retrospective study included consecutive patients diagnosed with EC (stage I to IV) with surgeries between January 2010 and October 2020 at the Cancer Hospital of Shantou University Medical College.ResultsThe 2-sample MR surveys indicated no causal relationship between inflammatory cytokines and endometrial cancer. 780 cases (median age, 55.0 years ) diagnosed with EC were included in the cohort and followed up for an average of 6.8 years. Increased inflammatory parameters at baseline were associated with a higher FIGO stage and invasive EC risk (odds ratios [OR] 1.01 to 4.20). Multivariate-cox regression suggested that multiple inflammatory indicators were significantly associated with overall survival (OS) and progression-free survival (PFS) (P < 0.05). Nomogram models based on inflammatory risk and clinical factors were developed for OS and PFS with C-index of 0.811 and 0.789, respectively. LASSO regression for the validation supported the predictive efficacy of inflammatory and clinical factors on the long-term outcomes of EC.ConclusionsDespite the fact that the genetic surveys did not show a detrimental impact of inflammatory cytokines on the endometrial cancer risk, our cohort study suggested that inflammatory level was associated with the progression and long-term outcomes of EC. This evidence may contribute to new strategies targeted at decreasing inflammation levels during EC therapy.

Associations of biological age accelerations and genetic risk with incident endometrial cancer: a prospective analysis in UK Biobank.

Endometrial cancer (EC) is one of the gynecologic malignancy cancer with increasing incidence and mortality rates, partly due to aging populations and genetic risks. This study explores the associations between biological age accelerations (BAA) and risk of incident EC and assesses the joint effect of genetic factor and BAA. Based on the UK Biobank cohort, 132,315 women participants were included for primary analysis and 124,119 white participants for genetic risk analysis. Biological age(BA) was calculated using the Klemera-Doubal (KDM) and PhenoAge method based on clinical biomarkers. We calculated two metrics for BAA (including KDM residual and PhenoAge residual) using residual analysis, comparing them against chronological age. The risk of incident EC was evaluated using multivariable Cox proportional-hazards models, adjusting for relevant covariates. Polygenic risk scores (PRS) were computed from known EC-associated SNPs. Both KDM and PhenoAge residual, were significantly associated with increased EC risk. In fully adjusted models, the highest tertile of KDM and PhenoAge residual was significantly associated with incident EC compared with the lowest group, with HRs of 1.278 (P=0.0044) and 1.424 (P<0.0001), repectively. The population-attributable fractions were 7.84% for KDM residual (P=0.0044), 9.78% for PhenoAge residual (P=0.0005), and 8.47% for genetic risk (P=0.0005). Additionally, joint associations of BAA and genetic risk with incident EC was evaluated. Compared with low genetic risk and low BAA, high genetic risk and high BAA was significantly associated with the incidence of EC with HRs of up to 2.172 (95% CI 1.592-2.963) for KDM and 2.226 (95% CI 1.640-3.022) for PhenoAge. Overall, higher levels of PhenoAge residual were consistently associated with an increased risk of incident EC, regardless of genetic risk. BAA and genetics both enhance the risk of incident EC. The effect of the PhenoAge residual is greater than that of the investigated genes, which in turn is greater than that of the KDM residual. These findings highlight the importance of considering both BAA and genetic factors in EC prevention.

Associations of steps per day and step intensity with the risk of cancer: Findings from the Women's Health Accelerometry Collaboration cohort

ObjectiveAccumulating more steps/day is associated with a lower risk of cancer mortality and composite cancer outcomes. However, less is known about the relationship of steps/day with the risk of multiple site-specific cancers. MethodsThis study included >22,000 women from the Women's Health Accelerometry Collaboration Cohort (2011−2022), comprised of women from the Women's Health Study and Women's Health Initiative Objective Physical Activity and Cardiovascular Health Study. Steps/day and step intensity were collected with accelerometry. Incident cancer cases and deaths were adjudicated. Stratified Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of the associations of steps/day and step intensity with incident breast, colon, endometrial, lung, and ovarian cancers, a composite of 13 physical activity-related cancers, total invasive cancer, and fatal cancer. ResultsOn average, women were 73.4 years old, accumulated 4993 steps/day, and had 7.9 years of follow-up. There were small nonsignificant inverse associations with the risks of colon cancer (HR = 0.94, 95% CI: 0.83, 1.05), endometrial cancer (HR = 0.91, 95% CI: 0.82, 1.01), and fatal cancer (HR = 0.95 95% CI: 0.90, 1.00) per 1000 steps/day. More minutes at ≥40 steps/min and a faster peak 10- and 30-min step cadence were associated with a lower risk of endometrial cancer, but findings were attenuated after adjustment for body mass index and steps/day. ConclusionsAmong women 62–97 years, there were small nonsignificant inverse associations of colon, endometrial, and fatal cancer with more steps/day. Epidemiologic studies with longer follow-up and updated assessments are needed to further explore these associations.

Associations between Diabetes Mellitus and Selected Cancers.

Cancer is one of the major causes of mortality and is the second leading cause of death. Diabetes mellitus is a serious and growing problem worldwide, and its prevalence continues to grow; it is the 12th leading cause of death. An association between diabetes mellitus and cancer has been suggested for more than 100 years. Diabetes is a common disease diagnosed among patients with cancer, and evidence indicates that approximately 8-18% of patients with cancer have diabetes, with investigations suggesting an association between diabetes and some particular cancers, increasing the risk for developing cancers such as pancreatic, liver, colon, breast, stomach, and a few others. Breast and colorectal cancers have increased from 20% to 30% and there is a 97% increased risk of intrahepatic cholangiocarcinoma or endometrial cancer. On the other hand, a number of cancers and cancer therapies increase the risk of diabetes mellitus. Complications due to diabetes in patients with cancer may influence the choice of cancer therapy. Unfortunately, the mechanisms of the associations between diabetes mellitus and cancer are still unknown. The aim of this review is to summarize the association of diabetes mellitus with selected cancers and update the evidence on the underlying mechanisms of this association.

P-317 Risk of endometrial polyps and hyperplasia after tamoxifen treatment in women with breast cancer: a population-based study in Taiwan

Abstract Study question This study aimed to examine the association between tamoxifen treatment and incident risks of uterine disease among breast cancer patients in Taiwan. Summary answer We found tamoxifen treatment group may have greater risk of endometrial polyps and hyperplasia than unexposured group after adjusting for age and body mass index. What is known already In the worldwide Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) breast cancer treatment trail reported that the women continue tamoxifen up to 10 years, compared with 5 years may reduce breast cancer recurrence and mortality rate. However, tamoxifen use has been reported to be associated with the cumulative risk of subsequently endometrial cancer during 5–14 years was 3.1%. Specifically, several Western studies have showed that the high incidence of endometrial cancer in breast cancer survivors with tamoxifen treatment. Study design, size, duration We conducted a retrospective cohort study using population-based data from Taiwan Cancer Registry and the National Health Insurance Research Database (NHIRD), and the National Population Registry Data set from 2011 to 2020. Participants/materials, setting, methods A total 138,934 newly diagnosed breast cancer female patients with age greater than 18 years old were included. We further used a 1-to-1 propensity score matching to generate comparable exposure and un-exposure groups. Cox proportional hazard regression models were used to examine the research question. All statistical analysis was performed using SAS version 9.4, and p-values &amp;lt; 0.05 were considered statistically significant Main results and the role of chance Incidence rate ratio (IRR) to compare incidence rate of uterine disease between tamoxifen treatment groups and unexposed group, adjusting for age and BMI. Our results showed that IRR were 1.36, 0.33, 3.73, 0.63, endometrial polyps, endometrial carcinoma, endometrial hyperplasia and uterine carcinosarcoma, respectively. This study found possible correlations between tamoxifen exposure with endometrial polyps and hyperplasia among breast cancer. During the 10-year study period, tamoxifen group did not significantly increase the risk of endometrial cancer in breast cancer survivors at aged 40 and over. Limitations, reasons for caution Our cohort study with 10-year period is its short study period, Tamoxifen group did not significantly increase the risk of endometrial cancer. Wider implications of the findings This cohort study found higher endometrial polyps and hyperplasia incidence rates among women with breast cancer who received tamoxifen women than those not treated with tamoxifen. Results of this study suggest that clinicians should consider the risk of uterine disease among tamoxifen use and counsel patients accordingly. Trial registration number KMUHIRB-G(II)20200217

High prevalence of dysfunctional uterine bleeding in candidates for metabolic/bariatric surgery: increased endometrial cancer risk?

BackgroundEndometrial cancer (EC) is the strongest obesity-associated malignancy and the fastest-growing cancer in young women. Early identification of EC and other endometrial pathology (malignant and nonmalignant) in women with severe obesity may improve treatment options and uterine preservation. Screening for endometrial pathology using abnormal or postmenopausal uterine bleeding (APUB) as a surrogate in women pursuing metabolic/bariatric surgery may be clinically beneficial, but data supporting this effort are limited. ObjectiveTo develop and institute a screening program for APUB as a surrogate for endometrial pathology in bariatric surgery candidates. SettingTwo, academic metabolic/bariatric surgery programs in Louisiana, United States. MethodsThe Modified SAMANTA is a 10-item questionnaire that was implemented to identify patients with APUB, specifically combining tools designed to identify anovulatory/postmenopausal and heavy menstrual bleeding. Demographic (age, race), body mass index, and questionnaire data were analyzed with respect to positive screening using data from March 2021 through May 2023. ResultsOf 1371 eligible women presenting for surgical evaluation, 664 (48.4%) positive screens were identified and referred for gynecologic evaluation to rule out endometrial hyperplasia/cancer or other endometrial pathology. The likelihood of positive screening for APUB was associated with increasing BMI (P = .001) and Black/African American race (P = .003), as well as increasing SAMANTA score (P < .001). In contrast, risk of positive screening was negatively associated with increasing age (P < .001). ConclusionsWomen presenting for metabolic/bariatric surgery have a high prevalence of APUB and, given this dysfunctional bleeding and concurrent obesity, are at greater risk for underlying EC. Potential risk factors for APUB, given their associations with screening positive, include increased body mass index, younger age, and Black/African American race. Standardized screening with appropriate gynecologic referral should be a routine part of the overall evaluation for women with severe obesity.