Mendelian randomization studies of gastric cancer reveal potential risk factors, promising biomarkers and therapeutic targets
Abstract 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...
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Springer
2025-06-01
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| Series: | Discover Oncology |
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| Online Access: | https://doi.org/10.1007/s12672-025-02954-w |
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| author | Maowei He Yanting Duan Yuanyan Zhang Chao Qian Jiawei Jin |
| author_facet | Maowei He Yanting Duan Yuanyan Zhang Chao Qian Jiawei Jin |
| author_sort | Maowei He |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-2a76c66d59a44650a5694938b60d3d82 |
| institution | OA Journals |
| issn | 2730-6011 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Springer |
| record_format | Article |
| series | Discover Oncology |
| spelling | doaj-art-2a76c66d59a44650a5694938b60d3d822025-08-20T02:10:38ZengSpringerDiscover Oncology2730-60112025-06-0116111510.1007/s12672-025-02954-wMendelian randomization studies of gastric cancer reveal potential risk factors, promising biomarkers and therapeutic targetsMaowei He0Yanting Duan1Yuanyan Zhang2Chao Qian3Jiawei Jin4Department of General Surgery, Beilun District People’s HospitalDepartment of Radiology, Beilun District People’s HospitalDepartment of General Surgery, Beilun District People’s HospitalDepartment of General Surgery, Beilun District People’s HospitalDepartment of General Surgery, Beilun District People’s HospitalAbstract 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.https://doi.org/10.1007/s12672-025-02954-wGastric cancerRisk factorsMendelian randomizationGenetic instrumentsMolecular dockingBiomarkers |
| spellingShingle | Maowei He Yanting Duan Yuanyan Zhang Chao Qian Jiawei Jin Mendelian randomization studies of gastric cancer reveal potential risk factors, promising biomarkers and therapeutic targets Discover Oncology Gastric cancer Risk factors Mendelian randomization Genetic instruments Molecular docking Biomarkers |
| title | Mendelian randomization studies of gastric cancer reveal potential risk factors, promising biomarkers and therapeutic targets |
| title_full | Mendelian randomization studies of gastric cancer reveal potential risk factors, promising biomarkers and therapeutic targets |
| title_fullStr | Mendelian randomization studies of gastric cancer reveal potential risk factors, promising biomarkers and therapeutic targets |
| title_full_unstemmed | Mendelian randomization studies of gastric cancer reveal potential risk factors, promising biomarkers and therapeutic targets |
| title_short | Mendelian randomization studies of gastric cancer reveal potential risk factors, promising biomarkers and therapeutic targets |
| title_sort | mendelian randomization studies of gastric cancer reveal potential risk factors promising biomarkers and therapeutic targets |
| topic | Gastric cancer Risk factors Mendelian randomization Genetic instruments Molecular docking Biomarkers |
| url | https://doi.org/10.1007/s12672-025-02954-w |
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