Background: Immune cell infiltration plays a critical role in regulating peptic ulcer disease (PUD) and gastrointestinal cancer (GC). However, regulators of the cell signaling hubs remain unclear. Aim: This study characterizes genes that are differentially expressed in PUD and GC tissue samples. Bioinformatics is used to define the immune-associated hub genes associated with the malignant transfer process of PUD to GC. Methods: Total expression data from PUD and early-stage GC tissue samples were obtained from GEO and TCGA. Differentially expressed genes were assessed and immunological enrichment analysis was performed. Protein-protein interaction (PPI) and Cytoscape analysis were used together to identify the hub genes. CIBERSORT and COX analysis were used to analyze the differentially infiltrated immune cell landscapes and determine HR scores of the hub genes. Results: Expression data identified 437 DEGs as common to both GC and PUD tissue. Of these, 49 immune-related DEGs were grouped by function, and seven hub genes were identified by PPI analysis. The NRP2 and SEMA3D genes were then selected for survival analysis. SEMA3D had a higher hazard ratio than NRP2 and was defined as the hub for PUD carcinogenesis. Conclusion: SEMA3D was characterized as the hub gene for PUD carcinogenesis.