Mendelian randomization studies of gastric cancer reveal potential risk factors, promising biomarkers and therapeutic targets.

Objective: To further understand the causal relationship between potential risk factors or biomarkers and gastric cancer, we performed an extensive Mendelian randomization (MR) analysis.

Methods: Genetic instruments were extracted from 486 available traits in 24 subcategories from the MR-Base platform, and ordinary two-sample MR, reverse MR, and mediating effect analyses were conducted based on 6563 gastric cancer cases and 195,745 controls from the BioBank Japan Project. We also performed Cox proportional hazards survival analysis, extensive phenotypic MR analysis, and molecular docking to evaluate potential biomarkers that may serve as therapeutic targets.

Results: Five identified risk factors were significantly associated with gastric cancer, including ulcerative colitis, vascular endothelial growth factor receptor 2 (VEGFR2), promotilin, neutrophil collagenase, and tyrosine-protein kinase receptor Tie-1 (soluble). The Cox proportional hazards survival analysis of the response genes KDR, MLN, MMP8, and TIE1 showed significant results in overall survival, first progression, and post-progression survival. The extensive phenotypic MR analysis found two associations with significant detrimental effects for targeting promotilin, including celiac disease and intestinal malabsorption (non-celiac), which showed beneficial effects for targeting neutrophil collagenase, and two associations with significant beneficial effects for targeting tyrosine-protein kinase receptor Tie-1, including hemorrhoids and functional digestive disorders. No significant associations were found for targeting VEGFR2. In addition, the results of chemotherapeutic sensitivity analysis and molecular docking of potential drugs with target genes also provide sufficient evidence for their important role in the treatment of gastric cancer.

Conclusion: In conclusion, risk factor-associated genes KDR, MLN, MMP8, and TIE1 might be promising targets for the prevention and treatment of gastric cancer. These findings provide new insights into the causal factors of gastric cancer and new directions for the development of targeted therapies.