Ovarian cancer risk according to circulating zinc and copper concentrations: A meta-analysis and Mendelian randomization study

Ovarian cancer is a lethal disease with few modifiable risk factors. Circulating zinc and copper are potential biomarkers for ovarian cancer; however, evidence of their causal effects are scarce. This study aimed to examine the impact of circulating zinc and copper concentrations on ovarian cancer risk, using meta-analysis and Mendelian randomization (MR) approaches.Twenty case-control studies, including 699 patients with ovarian cancer, 567 patients with benign ovarian lesions, and 1194 healthy controls, were selected for meta-analysis. With a Two-sample MR approach, genetic instruments of 21 single nucleotide polymorphisms (SNPs) associated with circulating zinc and 25 SNPs associated with circulating copper were created. Their genetic associations with ovarian cancer were extracted from a genome-wide association study of 25,509 ovarian cancer cases and 40,941 controls.Ovarian cancer patients had significantly lower concentrations of circulating zinc than healthy controls (Standardized mean differences [SMD] = -1.01, 95% CI: -1.38 to -0.64). In contrast, circulating copper concentrations were significantly higher in ovarian cancer patients (SMD = 1.46, 95% CI: 0.82 to 2.09). In MR analysis, we only found increased circulating zinc concentration causally associated with a lower risk of ovarian cancer (odds ratio = 0.968, 95% CI: 0.941 to 0.995, per SD of ranked-inverse normalized concentration), especially in the high-grade serous subtype.Although increased circulating copper and decreased zinc concentrations were found in ovarian cancer patients, a suggestive causal association was only detected with zinc concentration, suggesting further studies on zinc interventions for ovarian cancer might have clinical impact.