scholarly journals A genetic perspective on the relationship between non-cancerous gynecological diseases and endometrial cancer

2020 ◽  
Author(s):  
Pik Fang Kho ◽  
Sally Mortlock ◽  
Peter A.W. Rogers ◽  
Dale R. Nyholt ◽  
Grant W. Montgomery ◽  
...  
Keyword(s):  
Risk Factors ◽  
Endometrial Cancer ◽  
Cancer Risk ◽  
Genetic Correlation ◽  
Genetic Risk ◽  
Uterine Fibroids ◽  
Endometrial Cancer Risk ◽  
Gynecological Diseases ◽  
The Relationship ◽  
Shared Genetic

AbstractThe non-cancerous gynecological diseases, endometriosis, polycystic ovary syndrome (PCOS) and uterine fibroids, have been proposed as endometrial cancer risk factors; however, disentangling their relationships is complicated due to their shared risk factors and comorbidity. Using genome-wide association study (GWAS) summary data, we have explored the relationship between these non-cancerous gynecological diseases and endometrial cancer risk, assessing genetic correlations, causal relationships and shared genetic risk regions. Firstly, we found significant genetic correlation between endometrial cancer and PCOS (rG = 0.36, se = 0.12, P = 1.6×10−3), and uterine fibroids (rG = 0.24, se = 0.09, P = 5.4×10−3). Adjustment for genetically predicted body mass index (BMI; a risk factor for PCOS, uterine fibroids and endometrial cancer) substantially attenuated the genetic correlation between endometrial cancer and PCOS, but not uterine fibroids. Despite the observed genetic correlation, genetic causal inference tests (latent causal variable and Mendelian randomization analyses) did not support a causal relationship between any of the non-cancerous gynecological diseases and endometrial cancer. Gene-based association analysis revealed four shared endometriosis and endometrial cancer risk loci (9p21.3, 15q15.1, 17q21.32 and 3q21.3) and two shared uterine fibroid and endometrial cancer risk loci (5p15.33 and 11p13). In summary, we have shown that PCOS and uterine fibroids are genetically correlated with endometrial cancer, although the genetic architecture shared between endometrial cancer and PCOS likely relates to BMI. Furthermore, shared genetic risk regions, and thus potentially shared causal genes, were identified between the risk for endometrial cancer and endometriosis, and uterine fibroids.

scholarly journals Identifying molecular mediators of the relationship between body mass index and endometrial cancer risk: a Mendelian randomization analysis

2021 ◽  
Author(s):  
Emma Hazelwood ◽  
Eleanor Sanderson ◽  
Vanessa Y Tan ◽  
Katherine S Ruth ◽  
Timothy M Frayling ◽  
...  
Keyword(s):  
Risk Factors ◽  
Endometrial Cancer ◽  
Cancer Risk ◽  
Mendelian Randomization ◽  
Endometrial Cancer Risk ◽  
Mediating Role ◽  
Bioavailable Testosterone ◽  
The Relationship ◽  
Randomization Analysis

Background: Endometrial cancer is the most common gynaecological cancer in high-income countries. Elevated body mass index (BMI) is an established modifiable risk factor for this condition and is estimated to confer a larger effect on endometrial cancer risk than any other cancer site. However, the molecular mechanisms underpinning this association remain unclear. We used Mendelian randomization (MR) to evaluate the causal role of 14 molecular risk factors (hormonal, metabolic, and inflammatory markers) in endometrial cancer risk. We then evaluated and quantified the potential mediating role of these molecular traits in the relationship between BMI and endometrial cancer. Methods and Findings: Genetic instruments to proxy 14 molecular risk factors and BMI were constructed by identifying single-nucleotide polymorphisms (SNPs) reliably associated (P < 5.0 x 10-8) with each respective risk factor in previous genome-wide association studies (GWAS). Summary statistics for the association of these SNPs with overall and subtype-specific endometrial cancer risk (12,906 cases and 108,979 controls) were obtained from a GWAS meta-analysis of the Endometrial Cancer Association Consortium (ECAC), Epidemiology of Endometrial Cancer Consortium (E2C2), and UK Biobank. SNPs were combined into multi-allelic models and odds ratios (ORs) and 95% confidence intervals (95% CIs) were generated using inverse-variance weighted random-effects models. The mediating roles of the molecular risk factors in the relationship between BMI and endometrial cancer were then estimated using multivariable MR. In MR analyses, there was strong evidence that BMI (OR per SD increase: 1.88, 95% CI: 1.69 to 2.09, P = 3.87 x 10-31), total testosterone (OR per inverse normal transformed nmol/L increase: 1.64, 95% CI: 1.43 to 1.88, P = 1.71 x 10-12), bioavailable testosterone (OR per inverse normal transformed nmol/L increase: 1.46, 95% CI: 1.29 to 1.65, P = 3.48 x 10-9), fasting insulin (OR per natural log transformed pmol/L increase: 3.93, 95% CI: 2.29 to 6.74, P = 7.18 x 10-7) and sex hormone-binding globulin (SHBG, OR per inverse normal transformed nmol/L increase: 0.71, 95% CI: 0.59 to 0.85, P = 2.07 x 10-4) had a causal effect on endometrial cancer risk. Additionally, there was suggestive evidence that total serum cholesterol (OR per mg/dL increase: 0.90, 95% CI: 0.81 to 1.00, P = 4.01 x 10-2) had an effect on endometrial cancer risk. In mediation analysis using multivariable MR, we found evidence for a mediating role of fasting insulin (19% total effect mediated, 95% CI: 5 to 34%, P = 9.17 x 10-3), bioavailable testosterone (15% mediated, 95% CI: 10 to 20%, P = 1.43 x 10-8), and SHBG (7% mediated, 95% CI: 1 to 12%, P = 1.81 x 10-2) in the relationship between BMI and endometrial cancer risk. The primary limitations of this analysis include the assumption of linear relationships across univariable and multivariable analyses and the restriction of analyses to individuals of European ancestry. Conclusions: Our comprehensive Mendelian randomization analysis provides insight into potential causal mechanisms linking BMI with endometrial cancer risk and suggests pharmacological targeting of insulinemic and hormonal traits as a potential strategy for the prevention of endometrial cancer.

scholarly journals Multi-trait genome-wide association study identifies novel endometrial cancer risk loci that are associated with obesity or female testosterone levels

2021 ◽  
Author(s):  
Xuemin Wang ◽  
Pik Fang Kho ◽  
Dhanya Ramachandran ◽  
Cemsel Bafligil ◽  
Frederic Amant ◽  
...  
Keyword(s):  
Risk Factors ◽  
Endometrial Cancer ◽  
Cancer Risk ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Cancer Susceptibility ◽  
Genome Wide Association ◽  
Endometrial Cancer Risk ◽  
Cancer Risk Factors ◽  
Genome Wide

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.

A survey of patient knowledge on contraception and endometrial cancer risk factors

2020 ◽  
Vol 159 ◽  
pp. 238-239
Author(s):  
S. Patel ◽  
O.D. Lara ◽  
R. Tsai ◽  
M.Y. Williams-Brown
Keyword(s):  
Risk Factors ◽  
Endometrial Cancer ◽  
Cancer Risk ◽  
Patient Knowledge ◽  
Endometrial Cancer Risk ◽  
Cancer Risk Factors

Knowledge of endometrial cancer risk factors in a general gynecologic population

2020 ◽  
Vol 158 (1) ◽  
pp. 137-142 ◽  
Author(s):  
Christina R. Washington ◽  
Ashley Haggerty ◽  
Wanda Ronner ◽  
Pamela M. Neff ◽  
Emily M. Ko
Keyword(s):  
Risk Factors ◽  
Endometrial Cancer ◽  
Cancer Risk ◽  
Endometrial Cancer Risk ◽  
Cancer Risk Factors

scholarly journals Insulin/IGF and sex hormone axes in human endometrium and associations with endometrial cancer risk factors

2016 ◽  
Vol 27 (6) ◽  
pp. 737-748 ◽  
Author(s):  
Melissa A. Merritt ◽  
Howard D. Strickler ◽  
Mark H. Einstein ◽  
Hannah P. Yang ◽  
Mark E. Sherman ◽  
...  
Keyword(s):  
Risk Factors ◽  
Endometrial Cancer ◽  
Cancer Risk ◽  
Sex Hormone ◽  
Human Endometrium ◽  
Endometrial Cancer Risk ◽  
Cancer Risk Factors

scholarly journals Oral Bisphosphonate Use and Risk of Postmenopausal Endometrial Cancer

2015 ◽  
Vol 33 (10) ◽  
pp. 1186-1190 ◽  
Author(s):  
Polly A. Newcomb ◽  
Michael N. Passarelli ◽  
Amanda I. Phipps ◽  
Garnet L. Anderson ◽  
Jean Wactawski-Wende ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Cancer Risk ◽  
Postmenopausal Women ◽  
Treatment Of Osteoporosis ◽  
Endometrial Cancer Risk ◽  
Patients With Cancer ◽  
Oral Bisphosphonate ◽  
Intact Uterus ◽  
The Relationship

Purpose Bisphosphonates are common medications used for the treatment of osteoporosis and are also used to reduce metastases to bone in patients with cancer. Several studies, including the Women's Health Initiative (WHI), have found that use of bisphosphonates is associated with reduced risk of developing breast cancer, but less is known about associations with other common malignancies. This study was aimed at examining the effects of bisphosphonates on the risk of endometrial cancer. Methods We evaluated the relationship between use of oral bisphosphonates and endometrial cancer risk in a cohort of 89,918 postmenopausal women participating in the WHI. A detailed health interview was conducted at baseline, and bisphosphonate use was ascertained from an inventory of regularly used medications at baseline and over follow-up. All women had an intact uterus at the time of study entry. Results During a median follow-up of 12.5 years, 1,123 women were diagnosed with incident invasive endometrial cancer. Ever use of bisphosphonates was associated with reduced endometrial cancer risk (adjusted hazard ratio, 0.80; 95% CI, 0.64 to 1.00; P = .05), with no interactions observed with age, body mass index, or indication for use. Conclusion In this large prospective cohort of postmenopausal women, bisphosphonate use was associated with a statistically significant reduction in endometrial cancer risk.

scholarly journals Endometrial Cancer Risk Factors by 2 Main Histologic Subtypes

2012 ◽  
Vol 177 (2) ◽  
pp. 142-151 ◽  
Author(s):  
Hannah P. Yang ◽  
Nicolas Wentzensen ◽  
Britton Trabert ◽  
Gretchen L. Gierach ◽  
Ashley S. Felix ◽  
...  
Keyword(s):  
Risk Factors ◽  
Endometrial Cancer ◽  
Cancer Risk ◽  
Endometrial Cancer Risk ◽  
Cancer Risk Factors ◽  
Histologic Subtypes

Knowledge of Endometrial Cancer Risk Factors in a General Gynecologic Population

2020 ◽  
Vol 75 (10) ◽  
pp. 604-605
Author(s):  
Christina R. Washington ◽  
Ashley Haggerty ◽  
Wanda Ronner ◽  
Pamela M. Neff ◽  
Emily M. Ko
Keyword(s):  
Risk Factors ◽  
Endometrial Cancer ◽  
Cancer Risk ◽  
Endometrial Cancer Risk ◽  
Cancer Risk Factors

scholarly journals MON-LB004 Understanding the Influence of Endometrial Cancer Risk Factors Using Human Primary Endometrial Organoids

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Alina R Murphy ◽  
Hannes Campo ◽  
Julie Kim
Keyword(s):  
Risk Factors ◽  
Endometrial Cancer ◽  
Cancer Risk ◽  
Real Time ◽  
High Serum ◽  
Protective Effects ◽  
Endometrial Cancer Risk ◽  
Cancer Risk Factors ◽  
Increased Risk ◽  
Real Time Qpcr

Abstract It is unclear how endometrial cancer risk factors such as obesity, high serum testosterone, and high serum levels of the endocrine-disrupting compound bisphenol-A (BPA) influence hormone action to promote carcinogenesis. We hypothesized that obesity, high testosterone, and BPA exposure alters the protective progesterone response in the benign endometrium. Primary human benign endometrial organoids, consisting of both epithelial and stromal cells, were exposed to each of these risk factors in vitro in the presence of cyclic levels of estradiol, progesterone, and testosterone for 14 days. Progesterone response genes HSD17B2, IGFBP1, PAEP, and PRL were measured by real-time qPCR and IHC. First, to simulate obesity, endometrial organoids were cocultured with increasing numbers of human adipocyte spheroids during the hormone treatment. Real-time qPCR analysis revealed dysregulation of expression of HSD17B2 and IGFBP1 by approximately 20% when cocultured with 30 adipocyte spheroids. In addition, PRL protein levels were significantly lower in the stroma of the endometrial organoids. Second, increasing concentrations of BPA and 3nM testosterone individually or in combination were added to endometrial organoids together with the 14-day menstrual cycle hormones. Treatment with 0.6 ng/mL of BPA decreased expression of HSD17B2, IGFBP1, and PAEP by 50% to 80%. However, this effect was not seen in the context of high testosterone, indicating that there may be crosstalk between these two risk factors. In summary, this study demonstrated that adipocytes, BPA exposure, and high testosterone directly alter progesterone action in benign endometrial organoids, suggesting a diminution of the protective effects of progesterone and an increased risk of endometrial cancer.

scholarly journals Plasma Adiponectin Levels and Endometrial Cancer Risk in Pre- and Postmenopausal Women

2007 ◽  
Vol 92 (1) ◽  
pp. 255-263 ◽  
Author(s):  
Anne E. Cust ◽  
Rudolf Kaaks ◽  
Christine Friedenreich ◽  
Fabrice Bonnet ◽  
Martine Laville ◽  
...  
Keyword(s):  
Risk Factors ◽  
Endometrial Cancer ◽  
Cancer Risk ◽  
Postmenopausal Women ◽  
Binding Protein ◽  
Inverse Association ◽  
Endometrial Cancer Risk ◽  
Plasma Adiponectin ◽  
Igf Binding ◽  
Igf Binding Protein

Abstract Background: Adiponectin, an adipocytokine secreted by adipose tissue, is decreased in obesity, insulin resistance, type 2 diabetes, and polycystic ovary syndrome, all of which are well-established risk factors for endometrial cancer. Methods: We conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition to examine the relation between prediagnostic plasma adiponectin levels and endometrial cancer risk. Among pre- and postmenopausal women who were not currently using exogenous hormones, 284 women developed incident endometrial cancer during an average of 5.1 yr of follow-up. Using risk set sampling, 548 control subjects were selected, matched on center, age, menopausal status, phase of menstrual cycle, time of blood draw, and fasting status. Conditional logistic regression models were used to estimate relative risks and 95% confidence intervals. Results: Adiponectin levels were inversely associated with endometrial cancer risk [body mass index-adjusted relative risk for the top vs. bottom quartile = 0.56 (95% confidence interval 0.36–0.86), Ptrend = 0.006]. There was evidence of a stronger inverse association among obese women than among nonobese women (Pheterogeneity = 0.03). The inverse association also appeared stronger for women who were postmenopausal or perimenopausal than premenopausal at baseline, but this was not statistically significantly heterogeneous (Pheterogeneity = 0.51). The association remained statistically significant after separate adjustment for other obesity-related physiological risk factors such as C-peptide, IGF binding protein-1, IGF binding protein-2, SHBG, estrone, or free testosterone but only marginally statistically significant after simultaneous adjustment for these factors. Conclusions: High circulating adiponectin levels are associated with reduced endometrial cancer risk, largely independent of other obesity-related risk factors.

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