Premenopausal and postmenopausal obesity and endometrial cancer risk: circulating biomarkers of inflammation, insulin resistance, and sex hormones as mediators
JNCI: Journal of the National Cancer Institute, 2026
Wang S., Viallon V., Biessy C., O’Mara T., Kyrgiou M., Ellis L., Davidson E., Baker-Rand H., Yarmolinsky J., Keski-Rahkonen P., Johansson M., Fournier A., Canonico M., Naudin S., Turzanski Fortner R., Le Cornet C., Schulze M., Crous-Bou M., Sánchez M., Aizpurua A., Cabrera Castro N., Guevara M., Masala G., Tumino R., Giraudo M., Panico C., Travis R., Gunter M., Rinaldi S., Dashti S., Dossus L.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Oncology Metabolic Diseases Gynecology | Pathophysiology | Plasma |  Olink Target 96 |
Abstract
Background
Obesity may increase endometrial cancer risk through pathways involving chronic inflammation, insulin resistance, and altered sex hormone levels.
Methods
Within the European Prospective Investigation into Cancer and Nutrition cohort, we investigated these mediating pathways using prediagnostic 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 ≥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.
Results
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 (95% CI = 1.43 to 7.36) in the premenopausal analysis. Jointly, the ORNIE through all biomarkers was 1.82 (95% CI = 1.21 to 2.74; proportion mediated [PM] = 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, 95% CI = 1.02 to 1.41; PM = 15%) remained a key mediator beyond upstream biomarkers in the postmenopausal analysis and interleukin-6 (1.35, 1.03 to 1.78; 24%) remained a key mediator in the premenopausal analysis.
Conclusions
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.