Abstract
BACKGROUND: The mechanisms and risk factors underlying ovarian cancer (OC) remain under investigation, making the identification of new prognostic biomarkers and improved predictive factors critically important. Recently, circulating metabolites have shown potential in predicting survival outcomes and may be associated with the pathogenesis of OC. However, research into their genetic determinants is limited, and there are some inadequacies in understanding the distinct subtypes of OC. In this context, we conducted a Mendelian randomization study aiming to provide evidence for the relationship between genetically determined metabolites (GDMs) and the risk of OC and its subtypes. METHODS: In this study, we consolidated genetic statistical data of GDMs with OC and its subtypes through a genome-wide association study (GWAS) and conducted a two-sample Mendelian randomization (MR) analysis. The inverse variance weighted (IVW) method served as the primary approach, with MR-Egger and weighted median methods employed for cross-validation to determine whether a causal relationship exists between the metabolites and OC risk. Moreover, a range of sensitivity analyses were conducted to validate the robustness of the results. MR-Egger intercept, and Cochran's Q statistical analysis were used to evaluate possible heterogeneity and pleiotropy. False discovery rate (FDR) correction was applied to validate the findings. We also conducted a reverse MR analysis to validate whether the observed blood metabolite levels were influenced by OC risk. Additionally, metabolic pathway analysis was carried out using the MetaboAnalyst 5.0 software. RESULTS: In MR analysis, we discovered 18 suggestive causal associations involving 14 known metabolites, 8 metabolites as potential risk factors, and 6 as potential cancer risk reducers. In addition, three significant pathways, "caffeine metabolism," "arginine biosynthesis," and "citrate cycle (TCA cycle)" were associated with the development of mucinous ovarian cancer (MOC). The pathways "caffeine metabolism" and "alpha-linolenic acid metabolism" were associated with the onset of endometrioid ovarian cancer (OCED). CONCLUSIONS: Our MR analysis revealed both protective and risk-associated metabolites, providing insights into the potential causal relationships between GDMs and the metabolic pathways related to OC and its subtypes. The metabolites that drive OC could be potential candidates for biomarkers.