Association of the Genetic Variant VEGFA rs3025039 with Incidence and Prognosis of Cholangiocarcinoma

Background: Patients with cholangiocarcinoma (CCA) have a dismal prognosis, even when amenable to resection. We investigated genetic single-nucleotide polymorphisms (SNP) for their role in postoperative CCA prognosis, the susceptibility to CCA and in the tumor microenvironment.

Methods: Patients undergoing surgical CCA resection at Charité – Universitätsmedizin Berlin were genotyped for a SNP-panel including EGF, HIF1A, IL1B, VEGFA and ICAM1. Influence of the variants on population-based CCA susceptibility was investigated in UK Biobank. The role of intratumoral VEGFA expression and co-expression with other pathways was analyzed in an external iCCA dataset (Dong L.,Cancer Cell,2022).

Results: Of 221 patients undergoing CCA-surgery, 130 (58.8%) had intrahepatic and 91 (41.2%) perihilar CCA. Patients with the low-expression VEGFA T-allele (n=56/221, 25.3%) had longer cancer-specific survival in the full cohort (mean 88 months, 95%CI 71.7-104.5 vs. 67 months, 95%CI 51.4-82.4, p=0.007), and both longer cancer-specific and overall survival in the intrahepatic subgroup (83 months, 95%CI 63.5-103.8 vs. 48 months, 95%CI 36.9-59.8, p=0.040; 52 months, 95%CI 37.1-67.4 vs. 29 months, 95%CI 23.1-36.3, p=0.028, respectively). Lower intratumoral VEGFA expression (159/244, 65.2%) was associated with long-term mortality (2-year mortality 25.2% vs. 43.5%, log-rank p=0.001). Multivariate analysis confirmed prognostic independence in both datasets. Simultaneously, carriers of the T-allele had a higher risk of CCA in the community-based UK Biobank (OR, 1.27, 95%CI 1.08-1.49, p=0.003).

Conclusion: Both the presence of the low-expression VEGFA variant (rs3025039T) and low VEGFA expression identify subgroups of patients with mitigated oncologic and overall prognosis, while presence of the rs3025039T was associated with increased risk of CCA.

Publication History

Article published online:
20 January 2025