DNA methylation-mediated ADA overexpression drives pancreatic cancer progression

Pancreatic cancer (PC) is characterized by its aggressive nature, limited options for radiochemotherapy, and poor prognosis, highlighting the urgent need for the identification of novel therapeutic targets to broaden treatment strategies.

We employed a two-sample Mendelian randomization (MR) approach, utilizing genetically informed druggable genes to identify key genes associated with PC risk. To validate these candidate targets, we conducted sensitivity, colocaliztion, and summary data-based MR (SMR) analyses. Furthermore, DNA methylation mediation analysis was utilized to investigate upstream regulatory mechanisms of significant genes.

At a false discovery rate (FDR) of less than 0.05, five druggable genes were found to be significantly associated with PC. Through rigorous validation, adenosine deaminase (ADA) was identified as a potential contributor to increased PC risk. Mediation analysis indicated that higher methylation at cg20622019 was associated with lower ADA expression and reduced PC risk, with methylation mediating approximately 36% of the association between ADA and PC. Sensitivity analysis, SMR and Colocalization analysis supported our findings, demonstrating high statistical robustness.

This study identifies ADA as a prioritized, genetically supported druggable target for PC, supported by colocalization evidence (PPH4 = 0.7949), and elucidates the regulatory role of DNA methylation at the cg20622019 locus. Notably, other significantly screened genes (e.g., PDE2A) failed colocalization validation.