Premenopausal and postmenopausal obesity and endometrial cancer risk: circulating biomarkers of inflammation, insulin resistance, and sex hormones as mediators.

Abstract

Obesity may increase endometrial cancer risk through pathways involving chronic inflammation, insulin resistance, and altered sex hormone levels. Within the European Prospective Investigation into Cancer and Nutrition cohort, we investigated these mediating pathways using pre-diagnostic circulating biomarkers measured in 337 matched case-control pairs with postmenopausal measurements and 196 pairs with premenopausal measurements. We estimated the natural indirect effect (NIE) of obesity [body mass index (BMI) ≥30 kg/m2 vs < 25 kg/m2] on endometrial cancer risk: (1) for each biomarker separately, (2) for all biomarkers jointly, and (3) sequentially, accounting for upstream biomarkers based on an assumed causal sequence specified a priori. The adjusted odds ratio (OR) between obesity and endometrial cancer risk was 3.34 [95% confidence interval (CI) 1.97 to 5.65] in the postmenopausal analysis, and 3.24 (1.43 to 7.36) in the premenopausal analysis. Jointly, the ORNIE through all biomarkers was 1.82 [CI 1.21 to 2.74; proportion mediated (P.M.)=50%] in the postmenopausal analysis and 1.79 (0.97 to 3.29; 49%) in the premenopausal analysis. In sequential mediation analysis, estrone [ORNIE =1.20 (CI 1.02 to 1.41); P.M. = 15%] remained a key mediator beyond upstream biomarkers in the postmenopausal analysis and interleukin-6 (IL-6) [1.35 (1.03 to 1.78); 24%] remained a key mediator in the premenopausal analysis. Circulating biomarkers for inflammation, insulin resistance, and sex hormones may mediate the effect of obesity on endometrial cancer risk, with some overlaps in mediating pathways. Sex hormones were the most prominent mediators in postmenopausal obesity, whereas biomarkers for inflammation may play an important role in premenopausal obesity.