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This study identified 1565 DEGs and 3754 DEMGs in total. Of these, 369 were differentially expressed at both the gene and methylation levels. We identified 12 signature genes including VEGFC, FBP1, NR3C1, NFE2L2, and DFNA5 which were combined with the clinical data to produce a novel prognostic model for GC. This model could effectively split GC patients into two groups, high- and low-risk with these observations being confirmed in the validation dataset. The differential methylation of the 12 signature genes, including VEGFC, FBP1, NR3