Adiposity and Endometrial Cancer Risk in Postmenopausal Women: A Sequential Causal Mediation Analysis.
Dashti SG., English DR., Simpson JA., Karahalios A., Moreno-Betancur M., Biessy C., Rinaldi S., Ferrari P., Tjønneland A., Halkjær J., Dahm CC., Vistisen HT., Menegaux F., Perduca V., Severi G., Aleksandrova K., Schulze MB., Masala G., Sieri S., Tumino R., Macciotta A., Panico S., Hiensch AE., May AM., Quirós JR., Agudo A., Sánchez M-J., Amiano P., Colorado-Yohar S., Ardanaz E., Allen NE., Weiderpass E., Fortner RT., Christakoudi S., Tsilidis KK., Riboli E., Kaaks R., Gunter MJ., Viallon V., Dossus L.
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 and 2, and C-reactive protein (inflammatory status biomarkers); C-peptide (hyperinsulinemia biomarker); and free estradiol and estrone (estrogen biomarkers) in the adiposity-endometrial cancer link in postmenopausal women. METHODS:We used data from a case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC). Eligible women did not have cancer, hysterectomy, and diabetes; did not use oral contraceptives or hormone therapy; and were postmenopausal at recruitment. Mediating pathways from adiposity to endometrial cancer were investigated by estimating natural indirect (NIE) and direct (NDE) effects using sequential mediation analysis. RESULTS:The study included 163 cases and 306 controls. The adjusted OR for endometrial cancer for body mass index (BMI) ≥30 versus ≥18.5-<25 kg/m2 was 2.51 (95% confidence interval, 1.26-5.02). The ORsNIE were 1.95 (1.01-3.74) through all biomarkers [72% proportion mediated (PM)] decomposed as: 1.35 (1.06-1.73) through pathways originating with adiponectin (33% PM); 1.13 (0.71-1.80) through inflammation beyond (the potential influence of) adiponectin (13% PM); 1.05 (0.88-1.24) through C-peptide beyond adiponectin and inflammation (5% PM); and 1.22 (0.89-1.67) through estrogens beyond preceding biomarkers (21% PM). The ORNDE not through biomarkers was 1.29 (0.54-3.09). Waist circumference gave similar results. CONCLUSIONS:Reduced adiponectin and increased inflammatory biomarkers, C-peptide, and estrogens mediated approximately 70% of increased odds of endometrial cancer in women with obesity versus normal weight. IMPACT:If replicated, these results could have implications for identifying targets for intervention to reduce endometrial cancer risk in women with obesity.