Role of directly measured metabolic profile as an intermediate between adiposity and endometrial cancer: triangulation of evidence from independent sources.

Background Endometrial cancer (EC) is the most commonly diagnosed gynaecological cancer globally.

Adiposity is a major EC risk factor and as a consequence, the obesity epidemic is thought to have contributed to rising EC incidence.

Despite strong evidence linking adiposity and EC, mechanisms underlying the adiposity-EC relationship are incompletely understood and the impact of intentional weight loss on EC remains unresolved.

Adiposity alters systemic metabolism, leading to suggestions that a novel mechanism linking adiposity and EC could be adiposity-induced metabolic changes. Evidence for the effects of adiposity-altered metabolites in EC is scare. Evidence from our study suggests that metabolic signatures of adiposity were positively associated with EC.

However, the impact of adiposity on metabolic pathways in endometrial tissues is unclear.

Further, it is unclear whether weight loss promotes changes in the metabolic pathways linking adiposity and EC, and whether it lowers EC risk.

Aims Using a framework of existing data, resources and collaboration, this project will investigate whether specific metabolic pathways underlie the relationship between adiposity and EC by triangulating evidence from various sources of evidence.

Methods Prospective analyses using already available data from the European Prospective Investigation into Cancer and Nutrition (EPIC), Nurse’s Health Study I and II (NHSI/NHSII) and Prostate, Lung, Colorectal, Ovarian (PLCO)) (n=1280) to provide more robust estimates on the association between metabolites and EC risk.

Mendelian randomization (MR) analyses will evaluate the causal association between anthropometric measures and metabolic markers.

Profile comparison analyses will be conducted to map the metabolic precursors of EC risk to those of elevated adiposity.

To explore whether adiposity-driven metabolic pathways associated with EC are modified by weight loss interventions, we will measure metabolites in blood and endometrial tissue samples collected pre and post-weight loss intervention from at least 80 women with obesity.

Mediation analyses will quantify the proportion of the adiposity-EC relationship mediated by newly identified metabolic pathways as well as known pathways.

How the results of this research will be used Results generated from this work may have impact for the screening, prevention and treatment of EC, particularly for women with obesity at high risk of EC.

If suggested to be causal and modifiable, these pathways could be targeted by cancer prevention strategies that will also be relevant to other adiposity-related cancers.