Adiposity and Endometrial Cancer Risk in Postmenopausal Women: A Sequential Causal Mediation Analysis

Abstract Background: Adiposity increases endometrial cancer risk, possibly through inflammation, hyperinsulinemia, and increasing estrogens. We aimed to quantify the mediating effects of adiponectin (anti-inflammatory adipocytokine); IL6, IL1-receptor antagonist, TNF receptor 1 2, C-reactive protein (inflammatory status biomarkers); C-peptide (hyperinsulinemia biomarker); free estradiol estrone (estrogen biomarkers) in adiposity–endometrial link postmenopausal women. Methods: used data from a case–control study within European Prospective Investigation into Cancer Nutrition (EPIC). Eligible women did not have cancer, hysterectomy, diabetes; use oral contraceptives or hormone therapy; were at recruitment. Mediating pathways adiposity investigated by estimating natural indirect (NIE) direct (NDE) using sequential mediation analysis. Results: The included 163 cases 306 controls. adjusted OR for body mass index (BMI) ?30 versus ?18.5?<25 kg/m2 was 2.51 (95% confidence interval, 1.26–5.02). ORsNIE 1.95 (1.01–3.74) all biomarkers [72% proportion mediated (PM)] decomposed as: 1.35 (1.06–1.73) originating with (33% PM); 1.13 (0.71–1.80) inflammation beyond (the potential influence of) (13% 1.05 (0.88–1.24) (5% 1.22 (0.89–1.67) estrogens preceding (21% PM). ORNDE 1.29 (0.54–3.09). Waist circumference gave similar results. Conclusions: Reduced increased inflammatory biomarkers, C-peptide, approximately 70% odds obesity normal weight. Impact: If replicated, these results could implications identifying targets intervention reduce risk obesity.