Differential Effects of VEGFA and EGF Polymorphisms on Susceptibility and Postoperative Outcome in Cholangiocarcinoma

To investigate the impact of VEGFA and EGF genetic polymorphisms on postoperative survival, susceptibility, transcriptomics, and systemic proteomic regulation in cholangiocarcinoma (CCA).

Angiogenesis and growth factor signaling via vascular endothelial growth factor A (VEGFA) and epidermal growth factor (EGF) are key drivers of CCA biology, yet the clinical relevance of their genetic variants remains poorly defined.

A cohort of 221 patients undergoing curative-intent CCA resection at Charité-Berlin was analyzed. Patients were genotyped for 6 angiogenesis-related SNPs, including VEGFA rs3025039 and EGF rs4444903, and survival associations were assessed using Cox regression. The prognostic relevance of intratumoral VEGFA and EGF mRNA expression and pathway co-expression was evaluated in an independent transcriptomic cohort. Population-level associations with CCA susceptibility and serum proteomics were analyzed in the UK Biobank (n>500,000).

The VEGFA rs3025039 T allele was associated with improved cancer-specific survival, particularly in intrahepatic CCA, while the EGF rs4444903 G allele was linked to improved survival in perihilar CCA. High intratumoral VEGFA or EGF expression correlated with poorer survival in external validation, but this association was lost for EGF after multivariable adjustment. VEGFA -high tumors showed increased proliferative and suppressed immune transcriptional signatures, whereas EGF -high tumors displayed limited changes. UK Biobank analysis revealed increased intrahepatic CCA susceptibility among VEGFA T allele carriers, while the EGF G allele was associated with elevated circulating EGF levels.

VEGFA and EGF polymorphisms exert distinct effects on CCA, influencing disease susceptibility, postoperative outcomes, and systemic signaling, supporting their potential as biomarkers for clinical stratification.