Exploring the causality and pathogenesis of Type 2 diabetes in gastric cancer based on Mendelian randomization and transcriptome data analyses

Abstract Introduction: Gastric cancer (GC) is the fifth most common type of cancer in the world, and the relationship between type 2 diabetes mellitus (T2DM) and cancer risk has been a focus of attention. However, the causal relationship between the two and its pathogenesis are still highly controversial. Methods: Two-sample bidirectional Mendelian randomization (MR) and meta-analysis were used to explore the potential causal relationship between T2DM and GC. The sensitivity of the MR analysis was assessed by Cochran's Q test and the leave-one-out test. Next, transcriptome analyses of T2DM and GC patients were performed using The Cancer Genome Atlas and Gene Expression Omnibus databases to identify genes common to T2DM and GC and to construct a risk score and a prediction model for GC risk in combination with clinical features. KM curves and Cox regression were used for survival analysis, and the AUC values of the ROC curves were used for model evaluation. Mechanisms were explored by gene enrichment analysis and tumor immune microenvironment analysis. RESULTS: MR analysis revealed a causal relationship between T2DM and GC at the genetic level. In addition, the meta-analysis and sensitivity analysis confirmed the robustness of the current MR results. We constructed a prognostic risk score consisting of three T2DM-related genes (CST2, PSAPL1, and C4orf48). KM curves and Cox regression analyses suggested that OS was worse in patients with high risk scores (p < 0.05), and the constructed nomogram model had good predictive ability (training set: AUC = 0.786 and validation set: AUC = 0.757). Conclusion: Bidirectional MR two-sample analysis revealed that T2DM was a high-level risk factor for GC. Transcriptome data analysis revealed that the risk score, which reflects the expression of T2DM-related genes, can be used as a new marker to predict the prognosis of patients with coexisting T2DM. KEYWORDS: Gastric cancer, Type 2 diabetes, Mendelian randomization, Transcriptomic data, prevention