Exploring the Relationship Between Serological Metabolites and Oral Cancer: A Mendelian Randomization Study

Background: Oral cancer is a prevalent malignant tumor, comprising ∼5% to 6% of all tumors. The 5-year survival rate for this condition is ∼50%. However, the early symptoms of oral cancer are often inconspicuous and easily overlooked, leading to frequent misdiagnosis or missed diagnosis. Although some previous studies have investigated the correlation between oral cancer and serum metabolites, the exact relationship remains unclear. Consequently, it is of utmost importance to develop effective early diagnosis methods and explore the pathogenesis of oral cancer to enhance patients’ survival rates and quality of life. Methods: This Mendelian randomization (MR) study utilized the Genome-Wide Association Study (GWAS) catalog to obtain instrumental variables (IVs) that link 486 serum metabolites with oral cancer. The study then conducted a causal analysis, using serological metabolites as exposure factors and oral cancer as the outcome. The samples used in the study were exclusively from the European population. The main method used for the univariate MR analysis was the inverse variance weighting method. After excluding confounding factors, MR analysis was performed again. Sensitivity analyses were subsequently conducted to enhance the robustness of the MR results. Furthermore, metabolic pathway analysis was carried out on serum metabolites associated with oral cancer, aiming to identify and explore potential metabolic pathways. Results: After MR analysis, 8 serum metabolites were screened out that are highly correlated with the causal relationship with oral cancer, including androsterone sulfate (OR=2.11, 95% CI: 1.37–3.27, P =0.0007), X-12100--hydroxytryptophan (OR=0.12, 95% CI: 0.02–0.73, P =0.022), gamma-glutamylphenylalanine (OR=7.57, 95% CI: 1.17–48.85, P =0.033), 7-methylxanthine (OR=0.22, 95% CI: 0.05–0.90, P =0.035), urate (OR=12.03, 95% CI: 1.16–124.32, P =0.037), palmate (16:0) (OR=11.01, 95% CI: 1.11–109.13, P =0.040), creatinine (OR=0.03, 95% CI: 0.00–0.90, P =0.047), guanosine (OR=2.66, 95% CI: 1.00–7.04, P =0.049), and the absence of heterogeneity and horizontal pleiotropy in this study indicates that the MR results obtained are quite reliable. Conclusion: Androsterone sulfate, gamma-glutamylphenylalanine, urate, palmitate (16:0), creatinine, and guanosine have been identified as risk factors for oral cancer. In contrast, X-12100--hydroxytryptophan and 7-methylxanthine may have a protective effect against oral cancer. The findings of this study have significant implications for early oral cancer diagnosis and offer valuable insights into the disease’s pathogenesis.