The Prognostic Role of VEGFR-2 Gene Amplification in Relation to Serum AFP Levels Among Liver-Transplanted Patients with Hepatocellular Carcinoma

Abstract

Background Hepatocellular carcinoma (HCC) is the most common primary liver neoplasia. Vascular endothelial factor receptor 2 (VEGFR-2) plays an important role in angiogenesis and it has been associated with poor survival in certain other tumor types. Although a recent study also suggested an association between VEGFR-2 expression and HCC, the relationship between VEGFR-2 amplification and HCC is still obscure. Aim To evaluate prognostic role of vascular endothelial growth factor receptor 2 (VEGFR-2) amplification in relation to serum alpha-fetoprotein (AFP) levels and tumor clinicopathological parameters among liver-transplanted patients with HCC. Study design Cohort study Methods A total of 54 formalin-fixed paraffin-embedded and frozen HCC samples from patients who underwent liver transplantation between 2009 and 2015 were analyzed. VEGFR-2 amplification was determined via fluorescence in situ hybridization (FISH) method in tissue samples obtained during liver transplantation and analyzed with respect to serum AFP levels, tumor clinicopathological parameters, and oncological outcomes including recurrence free survival (RFS) and overall survival (OS). Results Amplified VEGFR-2 gene was prominent in 27 (50.0%) patients, while AFP levels were ≥100 ng/mL in 14 (25.9%) patients. Presence of amplified VEGFR-2 gene was associated with significantly shorter RFS time (mean 72.8 vs 101.3 months for positive and negative patients respectively, P = .015), whereas had no significant impact on OS time (median 79.2 vs 93.1 months, respectively, P = .206). Presence versus absence of amplified VEGFR-2 gene was associated with significantly higher levels of AFP (mean±SD 266.6±405.8 vs 40.6±94.6 ng/mL, P = .016) and higher recurrence rate (81.8 vs 18.2%, P = .018), and significantly predicted the AFP levels ≥100 ng/ml (OR, 10.2, 95%CI 1.8-56.9, P = .008). Lymphatic invasion and vascular invasion emerged as independent predictors of poor OS (HR, 12.4 [95% CI, 2.7-57.3], P = .01) and RFS (HR, 8.3 [95% CI, 2.3-29.8], P = .01). Conclusion In conclusion, our findings revealed the presence of amplified VEGFR-2 gene and its association with serum AFP elevation for the first time in HCC. VEGFR-2 amplification was associated with significantly shorter RFS and it emerged as a significant predictor of elevated AFP. Accordingly, our findings seem to indicate the role of AFP elevation in VEGFR-2-mediated tumorigenesis as well as the likelihood of amplified VEGFR-2 gene and high AFP levels to determine the risk status and efficacy of VEGFR-2-inhibitors in HCC liver transplanted patients.