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ObjectiveObservational studies have linked various serum and urinary biomarkers to cancer risk, but confounding and reverse causation limit causal inference. This study aimed to investigate the causal effects of 35 circulating biomarkers on the risk of 13 site-specific cancers.MethodsWe performed a comprehensive two-sample Mendelian randomization analysis using genetic instruments for 35 biomarkers from the UK Biobank (N = 363,228). Summary-level data for 13 cancers were obtained from the FinnGen consortium and IEU Open genome-wide association study. We employed inverse-variance weighted as the primary method, supplemented by sensitivity analyses. Significant associations were further scrutinized using bidirectional Mendelian randomization to rule out reverse causality and multivariable Mendelian randomization to assess independent effects.ResultsForward Mendelian randomization identified 49 associations. After false discovery rate correction, nine remained: colorectal cancer-nonalbumin protein (odds ratio = 0.86, 95% confidence interval: 0.80-0.93), total protein (odds ratio = 0.85, 95% confidence interval: 0.77-0.93), and uric acid (odds ratio = 0.89, 95% confidence interval: 0.83-0.97); gastric cancer-apolipoprotein B (odds ratio = 0.85, 95% confidence interval: 0.79-0.95) and low-density lipoprotein cholesterol (odds ratio = 0.87, 95% confidence interval: 0.79-0.95); liver cancer-gamma-glutamyl transferase (odds ratio = 1.29, 95% confidence interval: 1.11-1.50); breast cancer-high-density lipoprotein cholesterol (odds ratio = 1.08, 95% confidence interval: 1.04-1.13); and esophageal cancer-total cholesterol (odds ratio = 0.78, 95% confidence interval: 0.68-0.90). Reverse Mendelian randomization suggested no reverse causality except breast cancer on C-reactive protein. Multivariable Mendelian randomization confirmed 12 biomarkers with independent effects: liver cancer (cholesterol, gamma-glutamyl transferase, high-density lipoprotein cholesterol, and low-density lipoprotein); breast cancer (C-reactive protein, high-density lipoprotein cholesterol, and insulin-like growth factor 1); gastric cancer (apolipoprotein B, low-density lipoprotein, and sex hormone-binding globulin); colorectal cancer (insulin-like growth factor 1 and uric acid); plus single markers for thyroid cancer (blood urea nitrogen), cervical cancer (C-reactive protein), ovarian cancer (direct bilirubin), and endometrial cancer (sex hormone-binding globulin).ConclusionsThis large-scale Mendelian randomization study provides robust evidence supporting the tissue-specific causal roles of several circulating biomarkers in the pathogenesis of specific cancers. These findings enhance our understanding of cancer etiology and highlight potential biomarkers for risk assessment and prevention.