Increased Risk Of Endometrial Cancer Research Articles

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.

Deciphering the Role of Insulin-Like Growth Factor 1 in Endometrial Cancer in Patients With Polycystic Ovary Syndrome: Protocol for a Methodological Approach Using Cell Culture Experiments.

Endometrial cancer (EC) is the most common gynecological cancer in women globally. It is linked to increasing obesity rates and longer life spans. The molecular mechanisms leading to EC are unclear; however, women with polycystic ovary syndrome (PCOS) have a 3- to 5-fold increased EC risk. According to a pilot study conducted in the United Kingdom, insulin-like growth factor-1 (IGF-1) gene and protein were raised in the endometrium and blood of women with EC and PCOS, compared with those without PCOS (controls). Therefore, raised serum IGF-1 levels may contribute to an increased EC risk in women with PCOS, but it is necessary to test this hypothesis since not all studies have demonstrated this association. This study aims to investigate the role of IGF-1 in mediating EC risk in PCOS. This will be achieved by evaluating the proliferative effects of PCOS serum, IGF-1, and IGF-1 antagonist on human endometrial cancer 1-A and 1-B cell lines, with a comparison to controls (using serum from women without PCOS and cell culture media). The study will also identify differentially expressed genes and pathways activated by various treatments. We intend to recruit 20 women with PCOS and 20 women without PCOS for this cross-sectional study. All experiments will be carried out 4 times to ensure consistency. We will perform transcriptomic and phosphoproteomic profiling to identify differentially expressed genes and phosphoproteins between different treatments using RNA sequencing and phosphoproteomics. We will also perform bioinformatics pathway analysis to identify whether any unique collection of genes or phosphoproteins explains increased EC risk in PCOS. The primary outcome measure will be the cell proliferation (growth) difference measured by cell index values. Our protocol stands out due to its unique approach; no previous study has used this approach to investigate the oncogenic effect of serum from women with PCOS. Additionally, no previous study has considered the differential mutations of genes related to the insulin signaling pathway across various types of human EC cell lines and the potential impact of these variations on their experimental findings. Participants are currently being recruited. It is expected that preliminary findings suitable for analysis and publication will be available by the summer of 2024. Although we currently do not have any results to report, sharing our protocol at this stage will aid in research collaboration, provide an opportunity for early feedback, and help reduce duplication of effort by other research groups. The findings of our study will have broader implications. A deeper understanding of the mechanisms underlying the regulation of the IGF system in PCOS and EC will improve our ability to develop effective treatment modalities for EC and will be a vital step toward reducing EC in women globally. DERR1-10.2196/48127.

Endometrial cancer risk and trends among distinct African descent populations.

Endometrial cancer (EC) is the fourth most common cancer among Black women in the United States, a population disproportionately affected by aggressive nonendometrioid subtypes (e.g., serous, carcinosarcoma). To examine EC vulnerability among a wider spectrum of African descent populations, a comparison between Black women residing in different countries, rather than in the United States alone, is needed. The authors analyzed 34,789 EC cases from Florida (FL) (2005-2018), Martinique (2005-2018), and Guadeloupe (2008-2018) based on cancer registry data. Age-adjusted incidence rates, incidence rate ratios (IRRs), and annual percent changes (APC) in trends were estimated for Black populations residing in the United States (non-Hispanic Blacks [NHB]) and Caribbean. The US non-Hispanic White (NHW) population was used as a reference. Caribbean Black women had the lowest rates for endometrioid and nonendometrioid subtypes. Nonendometrioid types were most common among US (FL) NHBs (9.2 per 100,000), 2.6 times greater than NHWs (IRR, 2.60; 95% confidence interval [CI], 2.44-2.76). For endometrioid EC, rates increased 1.8% (95% CI, 0.1-3.5) yearly from 2005 to 2018 for US (FL) NHBs and 1.2% (95% CI, 0.9-1.6) for US (FL) NHWs whereas no change was observed for Caribbean Blacks. For nonendometroid carcinomas, rates increased 5.6% (95% CI, 4.0-7.2) among US (FL) NHB, 4.4% (95% CI, 0.3-8.6) for Caribbean Black, and 3.9% for US (FL) NHW women (95% CI, 2.4-5.5). Lower rates of nonendometrioid EC among Caribbean Black women suggest that vulnerability for these aggressive tumor subtypes may not currently be an overarching African ancestry disparity. Most importantly, there is an alarmingly increasing trend in nonendometrioid across all populations studied, which warrants further surveillance and etiological research for this particular subtype. We analyze population-based incidence rates and trends of endometrial cancer (EC) for African descent populations residing in different countries (i.e., United States, Martinique, Guadeloupe) to examine whether EC vulnerability among Black women is socio-environmental or more ancestry-specific in nature. The increased EC risk was not uniform across all Black women since the Caribbean had the lowest rates (for endometrioid and nonendometrioid histology subtypes). Regardless, from 2005 to 2018, there was an increasing trajectory of nonendometrioid EC for all groups, regardless of race.

Meta-Analysis of 49 SNPs Covering 25,446 Cases and 41,106 Controls Identifies Polymorphisms in Hormone Regulation and DNA Repair Genes Associated with Increased Endometrial Cancer Risk.

Endometrial cancer (EC) is among the most common gynecological disorders globally. As single nucleotide polymorphisms (SNPs) play an important role in the causation of EC, therefore, a comprehensive meta-analysis of 49 SNPs covering 25,446 cases and 41,106 controls was performed to identify SNPs significantly associated with increased EC risk. PubMed was searched to identify case control studies and meta-analysis was performed to compute the pooled odds ratio (OR) at 95% confidence interval (CI). Cochran's Q-test and I2 were used to study heterogeneity, based on which either a random or a fixed effect model was implemented. The meta-analysis identified 11 SNPs (from 10 genes) to be significantly associated with increased EC risk. Among these, seven SNPs were significant in at least three of the five genetic models, as well as three of the polymorphisms (rs1801320, rs11224561, and rs2279744) corresponding to RAD51, PGR, and MDM2 genes, which contained more than 1000 EC cases each and exhibited increased risk. The current meta-analysis indicates that polymorphisms associated with various hormone related genes-SULT1A1 (rs1042028), PGR (rs11224561), and CYP19A1 (rs10046 and rs4775936); DNA repair genes-ERCC2 (rs1799793), OGG1 (rs1052133), MLH1 (rs1800734), and RAD51 (rs1801320) as well as genes like MDM2 (rs2279744), CCND1 (rs9344), and SERPINE1 (rs1799889), are significantly associated with increased EC risk.

Polycystic Ovary Syndrome and Endometrial Cancer: A Scoping Review of the Literature on Gut Microbiota.

Gut dysbiosis has been associated with polycystic ovary syndrome (PCOS) and endometrial cancer (EC) but no studies have investigated whether gut dysbiosis may explain the increased endometrial cancer risk in polycystic ovary syndrome. The aim of this scoping review is to evaluate the extent and nature of published studies on the gut microbiota in polycystic ovary syndrome and endometrial cancer and attempt to find any similarities between the composition of the microbiota. We searched for publications ranging from the years 2016 to 2022, due to the completion date of the ‘Human Microbiome Project’ in 2016. We obtained 200 articles by inputting keywords such as ‘gut microbiome’, ‘gut microbiota’, ‘gut dysbiosis’, ‘PCOS’, and ‘endometrial cancer’ into search engines such as PubMed and Scopus. Of the 200 identified in our initial search, we included 25 articles in our final review after applying the exclusion and inclusion criteria. Although the literature is growing in this field, we did not identify enough published studies to investigate whether gut dysbiosis may explain the increased EC risk in PCOS. Within the studies identified, we were unable to identify any consistent patterns of the microbiome similarly present in studies on women with PCOS compared with women with EC. Although we found that the phylum Firmicutes was similarly decreased in women with PCOS and studies on women with EC, there was however significant variability within the studies identified making it highly likely that this may have arisen by chance. Further research pertaining to molecular and microbiological mechanisms in relation to the gut microbiome is needed to elucidate a greater understanding of its contribution to the pathophysiology of endometrial cancer in patients with polycystic ovarian syndrome.

Endometrial cancer risk factors in Singapore Chinese: a prospective cohort study

PurposeThe incidence of Endometrial cancer (EC) has grown substantially in Asia over the past decade. However, few studies have addressed risk factors associated with EC incidence in Asian populations. We explored the association between reproductive and dietary risk factors and EC in the Singapore Chinese Health Study (SCHS), one of the largest prospective cohort studies in Asia. MethodsData were collected from 34,028 ethnically Chinese women aged 45–74 residing in Singapore, enrolled between 1993 and 1998. Baseline demographic, dietary, and reproductive factors were collected via structured questionnaires. EC cases were identified from the Singapore Cancer Registry (n = 126) up to 2010. Cox proportional hazard models were used to analyze association between EC and personal, reproductive, and dietary factors. ResultsThe incidence of EC in this population was 28.8 per 100,000 person-years. Regardless of menopausal status, obesity (BMI ≥ 27) was associated with increased EC risk (HR = 2.22, 95% CI 1.26–3.92), while later age at menarche was associated with decreased EC risk (HR = 0.14, 95% CI 0.04–0.46). In postmenopausal women, later age at menopause was associated with increased EC risk (HR = 2.82, 95% CI 1.24–6.43). Lifestyle and nutritional factors were not associated with risk of EC in this cohort. ConclusionsThis study is one of the largest cohort studies exploring EC risk factors in Asian populations. Our study identified similarities in EC risk factors for European and Asian populations, which potentially suggests that strategies developed for EC prevention in Western populations can be potentially appropriate for the Singapore Chinese population due to risk factor similarities.

Risk of Endometrial Cancer in Women with Diabetes: A Population-Based Retrospective Cohort Study

The aim of this study was to examine the association between type 2 diabetes (T2DM), use of glucose-lowering medications and endometrial cancer (EC) risk. Methods: The risk of EC incidence among women with T2DM in Lithuania was assessed using a retrospective cohort study design. Female patients who were registered with T2DM between 1 January 2000 and 31 December 2012 were identified in the National Health Insurance Fund database. EC cases (ICD-10 code C54) were identified from the Lithuanian Cancer Registry. Standardized incidence ratios (SIRs) were calculated by dividing the observed numbers of EC among patients with T2DM by the expected number of EC, calculated using national rates. Results: A total of 77,708 diabetic women were included in the analysis, and 995 cases of EC were identified. A significantly increased EC risk in diabetic women was found as compared to the general population (SIR = 1.69, 95% CI 1.59–1.80). The greatest EC risk was found among younger patients at T2DM diagnosis, and the risk declined gradually with increasing age but persisted in being significantly increased among all age groups. The risk for EC increased with increasing duration of diabetes, and the highest EC risk was observed more than 10 years after T2DM diagnosis. A significantly higher EC risk than expected from the general population was found in all patient groups by glucose-lowering medication combinations. The lowest EC risk was observed in diabetic women who were users of “oral only” (without metformin) (SIR = 1.42, 95% CI 1.10–1.83) and “metformin only” (SIR = 1.69, 95% CI 1.49–1.92) medications. A two times greater EC risk was observed among the remaining glucose-lowering medication categories. In contrast, use of insulin only was not related to a higher EC incidence risk (SIR = 0.45, 95% CI 0.23–0.86); however, the risk estimation was based on nine cases. Conclusions: Our study shows a significantly increased EC risk in diabetic women as compared to the general population. In this study, a significantly higher EC risk was found in all patient groups by glucose-lowering medication combinations, except for insulin only users.

Association of TNFAIP8 gene polymorphisms with endometrial cancer in northern Chinese women

BackgroundTumor necrosis factor-a-induced protein 8 (TNFAIP8) presented a elevated expression in endometrial cancer (EC). However, the relationship of TNFAIP8 gene polymorphisms with EC risk remains unclear. This case–control study aimed to investigate the effect of single nucleotide polymorphisms (SNPs) in TNFAIP8 on northern Chinese women with EC.MethodsSNP rs11064, rs1045241, and rs1045242 in TNFAIP8 were successfully genotyped in 248 cancer-free controls and 226 ECs by SNaPshot method, respectively. Logistic regression was performed to assess relationship of SNPs with EC risk. The relationships of SNPs with clinicopathological variables were evaluated by Chi-square test or Student’s t-test or Fisher’s text.ResultsThe minor alleles of rs11064 in TNFAIP8 were strongly associated with EC risk, with adjust odds ratio (OR) of 1.719 (95% CI 1.180–2.506, P = 0.005). The minor allele of rs1045242 in the TNFAIP8 gene was strongly associated with with EC risk (adjust OR: 1.636, 95% CI 1.107–2.417, P = 0.014). rs11064 SNPs correlated with TNFAIP8 protein expression in EC (P = 0.015). For rs1045242, patients with AG + GG presented higher TNFAIP8 protein expression than that with AA (P = 0.020). It also showed that SNP rs11064 was associated with advanced FIGO stage (P = 0.001), deep myometrial invasion (P = 0.047), and lymph node metastasis (P = 0.048) under the codominant model in ECs.ConclusionsSNP rs11064 in TNFAIP8 increased EC risk and significantly related with its protein expression in northern Chinese women.

Impact of MDM2, TP53 and P14ARF Polymorphisms on Endometrial Cancer Risk and Onset.

The aim of this study was to determine the joint effect of single nucleotide polymorphisms (SNPs) of MDM2, TP53, and CDKN2A (P14ARF) genes on the onset and course of endometrial cancer (EC) in postmenopausal women. The study group consisted of 144 EC women and 50 non-cancer controls. MDM2 rs22279744, TP53 rs1042522, and P14ARF rs3088440, rs3731217, and rs3731245 SNPs were analysed. The double-SNP combinations T-C, T-T, or T-G in MDM2 SNP 309 and P14ARF polymorphisms decreased EC risk. The triple-SNP combinations T-C-T, T-C-G, or T-T-G in MDM2 SNP and two P14ARF polymorphisms decreased EC risk. The multiple-SNP combination T-C-T-G in MDM2 and three P14ARF polymorphisms decreased EC risk. The G-Arg-C-T-G carriers were at increased EC risk, while the T-Arg-C-T-G carriers were at decreased EC risk. MDM2 SNP309 plays a role in EC onset in postmenopausal women.

Is There Any Association between Glutathione S-transferases M1 and Glutathione S-transferases T1 Gene Polymorphisms and Endometrial Cancer Risk? A Meta-analysis.

Epidemiological evidence on the association between genetic polymorphisms in glutathione S-transferases M1 (GSTM1) and T1 (GSTT1) genes and risk of endometrial cancer (EC) has been inconsistent. In this meta-analysis, we seek to investigate the relationship between GSTM1 and GSTT1 polymorphisms and the risk of EC. We searched Medline, PubMed, Web of Science, Embase, Chinese National Knowledge Infrastructure database, and Chinese Biomedical Literature database to identify eligible studies. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) for the association were determined using a fixed- or random-effect model. Tests for heterogeneity of the results and sensitivity analyses were performed. A total of six case–control studies were included in the final meta-analysis of GSTM1 (1293 cases and 2211 controls) and GSTT1 (1286 cases and 2200 controls) genotypes. Overall, GSTM1 null genotype was not significantly associated with an increased risk of EC (OR = 1.00, 95% CI = 0.76–1.30, P = 0.982). Similarly, for GSTT1 deletion genotype, we observed no association under the investigated model in the overall analysis (OR = 0.91, 95% CI = 0.64–1.30, P = 0.619). Subgroup analysis also showed no significant association between the GSTM1 null genotype and EC risk in hospital-based design (OR = 1.26, 95% CI = 0.93–1.71, P = 0.131) and no relationship between GSTT1 null genotype with EC risk in population-based design (OR = 1.18, 95% CI = 0.79–1.76, P = 0.407). However, GSTM1 null genotype contributed to an increased EC risk in population-based design (OR = 0.76, 95% CI = 0.60–0.97, P = 0.027), while null GSTT1 in hospital-based studies (OR = 0.70, 95% CI = 0.52–0.93, P = 0.015). The present meta-analysis suggested that GSTs genetic polymorphisms may not be involved in the etiology of EC. Large epidemiological studies with the combination of GSTM1 null, GSTT1 null, and design-specific with the development of EC are needed to prove our findings.

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Epistatic interaction between adiponectin and survivin gene polymorphisms in endometrial carcinoma

Adiponectin appears to play an important role in the development and progression of several obesity-related malignancies. Also, overexpression of survivin, an inhibitor of apoptosis protein, is associated with increased risk of cancers. The aim of this study was to investigate the association between two polymorphisms in the adiponectin gene and endometrial cancer (EC) risk. We also investigated whether epistasis between surviving and adiponectin gene polymorphisms are associated with EC risk in an Iranian population.The samples comprised formalin-fixed, paraffin-embedded tissue sections obtained from the archive of the pathology department, Imam-Khomeini Hospital and Firouzgar hospital. After DNA extraction the genotyping was performed using PCR-RFLP technique.Single nucleotide polymorphisms (SNPs) in adiponectin (rs1063539, rs2241766) and survivin (rs9904341) gene were evaluated in the study. The increased frequency of ADIPOQ rs1063539C allele (CC+CG genotype) was associated with decreased EC risk [OR: 0.39(0.17–0.90)]. Survivin rs9904341C allele (CC+CG genotype) was associated with increased EC risk [crude OR: 2.75(1.27–5.95), adjusted OR: 2.93(1.27–6.76)]. We observed an epistatic interaction between survivin rs9904341 CC+CG genotype and ADIPOQ rs1063539 GG genotype increasing the risk of EC compared to those with other genotypes [OR: 4.86(1.88–12.54), P=0.001].Our findings indicate that adiponectin might have a modulatory effect on survivin role and function in EC, which requires further investigation.