Impact of SERPINA3 on the Prognostic Role of KRAS G12R-Mutated Pancreatic Ductal Adenocarcinoma Patients Receiving Gemcitabine-Based Treatment: A Cross-Sectional Study.

Background and Aims: Gemcitabine-based treatment is normally used for pancreatic ductal adenocarcinoma (PDAC). Genetic polymorphisms of the Kirsten rat and novel oncogene homologue (KRAS) variant contribute to the survival and prognosis of patients with PDAC. We aimed to reveal a potential gene signature against the background of KRAS mutations in PDAC after gemcitabine-based treatment. Methods: In this study, 35 PDAC patients were enrolled for analysis. The highly mutated genes were screened out. K‒M survival plots were then used to compare the effects of different KRAS variants on survival. The total expression data related to different KRAS genetic variants and PDAC samples treated with gemcitabine were extracted from the Cancer Genome Atlas Program (TCGA) and the Gene Expression Omnibus (GEO), respectively. The differentially expressed genes (DEGs) were identified, and the Gene Set Enrichment analysis (GSEA) was then performed. The hub genes between the selected TCGA and GEO data sets were extracted. K-M analysis and Linkomics-based method were used to evaluate the prognostic value of the hub genes. GSEA and the Tumor Immune Dysfunction and Exclusion (TIDE) database-based analysis were also employed. Results: KRAS Glycine (G) 12 Arginine (R) mutations are associated with shorter Progression-Free-Survival (PFS) than the other two KRAS mutational types. Five hub genes were screened out according to the above method. After the K‒M analysis, only SERPINA3 was identified as a hub gene according to the overall survival results (p < 0.05). The linkomics results indicated that the higher expression of the hub gene was positively correlated with KRAS mutations. GSEA and TIDE revealed that they were correlated with Cluster of Differentiation 4 Positive T Cell (CD4+ T cell) activation in opposite directions. Conclusions: SERPINA3 overexpression and KRAS G12R were together identified as novel gene signatures to predict poor PFS of PDAC patients receiving gemcitabine-based treatment.