Alternative Splicing in Pancreatic Ductal Adenocarcinoma Leads to Dysregulated Immune System

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy that poses a significant global health threat, marked by a substantial increase in prevalence and mortality rates. Accounting for 90 % of pancreatic cancer cases, PDAC carries a dismal prognosis, and current therapeutic approaches, including immunotherapy, face challenges due to poor immunogenicity. This study aimed to discover differentially expressed immune genes shared between PDAC and normal samples from two datasets obtained from the NCBI GEO Dataset. The RNA-seq pipeline was employed for gene expression analysis, and enrichR facilitated functional enrichment analysis of biologically and statistically significant genes. Predictions of immune infiltration cells and corresponding genes, along with their immune responses, were made using the ScType database and the immunedeconv package, respectively. Verification of gene expression levels was conducted through GEPIA2, Expression Atlas, and literature review. Additionally, isoform-switching analysis of dysregulated genes aimed to uncover alternatively spliced pathogenic isoforms in PDAC. Notably, four immune genes (EPHA2 upregulated, GNG11, CRHBP, and FCER1A downregulated) were found to be common in both datasets and were highly implicated in PDAC. The dysregulated immune genes influenced molecular functions, including protein binding, transmembrane receptor protein tyrosine kinase activity, protein tyrosine kinase activity, and cadherin binding for upregulated genes. Downregulated genes were associated with GTPase activity and ribonucleoside triphosphate phosphatase activity. This study suggests these immune genes as potential prognostic biomarkers for effective PDAC treatment. However, further investigations are essential to unravel the functional perspectives of potential isoforms.