Background

Endometrial cancer is the most common gynaecological cancer in high-income countries. Elevated body mass index (BMI) is an established risk factor and is estimated to confer a larger effect on endometrial cancer risk than any other cancer site. However, the mechanisms underpinning this association remain unclear. We used Mendelian randomization (MR) to evaluate the causal role of 14 previously reported molecular risk factors (hormonal, metabolic, and inflammatory markers) in endometrial cancer risk. We then evaluated and quantified the mediating role of these molecular traits in the relationship between BMI and endometrial cancer risk.

Method

Genetic instruments to proxy 14 molecular risk factors and BMI were constructed by identifying single-nucleotide polymorphisms (SNPs) strongly associated (P < 5 x 10^-8) with each risk factor in previously reported genome-wide association studies (GWAS). Summary genetic association data for endometrial cancer risk were obtained from a GWAS meta-analysis (12,906 cases and 108,979 controls). 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 risk factors in the relationship between BMI and endometrial cancer were then estimated using multivariable MR.

Results

There was strong evidence for a causal effect of BMI (per SD (4.7 kg/m²) increase: OR=1.83, 95% CI=1.65-2.03, P=7.11x10^-3), fasting insulin (per natural log transformed pmol/L increase: OR=3.93, 95% CI=2.29-6.74, P=7.18x10^-7), bioavailable testosterone (per inverse normal transformed nmol/L increase: OR=1.47, 95% CI=1.30-1.66, P=3.82x10^-10) and sex hormone-binding globulin (SHBG) (per inverse normal transformed nmol/L increase: OR=0.71, 95% CI=0.59-0.85, P=1.71x10^-4) on endometrial cancer risk. We found evidence for a mediating role of fasting insulin (15% mediated, 95% CI=4-17%, P=8.54x10^-3), bioavailable testosterone (17% mediated, 95% CI=12-23%, P=9.84x10^-10), and SHBG (7% mediated, 95% CI=2-13%, P=8.16x10^-3) in the relationship between BMI and endometrial cancer risk.

Conclusion

Our comprehensive analysis provides insight into potential causal mechanisms linking BMI with endometrial cancer risk and suggests pharmacological targeting of insulinemic and hormonal traits as a promising strategy for endometrial cancer prevention.

Impact statement

This analysis deciphers some of the causal mechanisms driving the effect of BMI on endometrial cancer risk, which could have important therapeutic implications for endometrial cancer prevention.