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

Abstract

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.

Mendelian randomization analysis of factors related to ovulation and reproductive function and endometrial cancer risk

“…We have performed the largest and most detailed MR analysis of factors related to ovulation and reproductive function and EC risk to date. We found a negative causal effect of the number of live births on a woman's risk of EC (OR: 0.783, 95% CI: 0.623, 0.985), independent of the causal effect from known risk factors such as age at menarche, age at menopause, and BMI [31][32][33]60], which has not been reported to date. These results attenuated compared to the effect of the number of live births on EC risk in the univariate analysis, suggesting some Fig.…”

“…MR is an epidemiological method that uses genetic variants as instrumental variables to investigate whether an observational association between an exposure and an outcome represents a causal relationship [27][28][29][30], and is robust to some of the limitations of observational epidemiological studies. Body mass index (BMI) is one such risk factor that has further been studied using MR and has been reported in several papers to causally increase the risk of EC [31][32][33]. One of which shows that fasting insulin, bioavailable testosterone, and sex hormone-binding globulin seem to mediate the relationship between BMI and EC risk [33].…”

“…Body mass index (BMI) is one such risk factor that has further been studied using MR and has been reported in several papers to causally increase the risk of EC [31][32][33]. One of which shows that fasting insulin, bioavailable testosterone, and sex hormone-binding globulin seem to mediate the relationship between BMI and EC risk [33].…”

RNA m6A methylation regulators in endometrial cancer (Review)

“…Obesity is also related to a high level of insulin. Higher levels of insulin and estrogen are associated with the risk of EC (25,26). However, the pathogenesis of EC remains to be fully elucidated.…”

Indikationsstellung in der Adipositastherapie – Surgeons first? // Indications in obesity therapy - surgeons first?

“…So haben z. B. Frauen, die ihr ganzes Leben übergewichtig waren, ein 2-fach höheres Risiko, an einem Endometriumkarzinom zu erkranken [6].…”