A Potential Target for Suppressing Pancreatic Cancer: PDGFRBRegulated by DNA Methylation

Introduction: Pancreatic Cancer (PC) remains highly lethal with limited treatment options. The causal roles of DNA methylation and protein Quantitative Trait Loci (pQTL) in its development are not fully understood, warranting further investigation into potential mechanisms and therapeutic targets. Methods: We integrated data from the IEU Open GWAS (n = 476,245), GoDMC (n = 27,750), and a large-scale pQTL study (n = 35,559) to perform Mendelian randomization (MR) analyses and identify potential causal genes and regulatory mechanisms for PC. The inverse variance weighted (IVW) method was used as the primary approach, with robustness assessed through a series of sensitivity analyses. Single-cell RNA sequencing data were used to validate gene expression patterns, and mediation analysis was applied to evaluate the role of gene expression in linking DNA methylation to PC risk. Results: MR analysis identified a significant inverse association between the Platelet-Derived Growth Factor Receptor Beta (PDGFRB) expression and PC risk(OR=0.9179, 95% CI=0.8837— 0.9535, P=9.96×10−6). Sensitivity analyses confirmed the absence of heterogeneity and pleiotropy. Notably, PDGFRB expression was enriched in pancreatic islet-derived single-cell RNA sequencing datasets, suggesting a potential protective role in pancreatic microenvironment homeostasis. Mediation analysis revealed that DNA methylation at locus cg11042320 mediated 97.62% of the association between PDGFRB and PC, underscoring its regulatory importance. Discussion: Using an integrative MR framework linking pQTLs, mQTLs, and single-cell data, we identify PDGFRB as a protective factor for pancreatic cancer, with cg11042320 methylation as a key upstream regulator. These results outline a causal path from methylation to expression to risk and suggest PDGFRB helps stabilize the tumor microenvironment. Clinically, PDGFRB expression and cg11042320 methylation may support risk stratification and selection of epigenetic or microenvironment-targeted therapies. Conclusion: Two-sample MR showsthat higher PDGFRB expression is associated with lower pancreatic cancer risk (IVW OR ≈0.92), primarily mediated by cg11042320 methylation (~98%), with findings robust to heterogeneity and pleiotropy tests. Together with single-cell evidence, these data prioritize PDGFRB and its epigenetic regulation as actionable targets and ensure functional and multi-ancestry validation.