Abstract
Vascular endothelial growth factor A (VEGFA) is an important angiogenesis regulator, which plays an important role in angiogenesis and progression of tumor, including hepatocellular carcinoma (HCC). We aimed at determining whether single nucleotide polymorphisms of VEGFA gene influence the development and clinical outcomes of HCC. We analyzed four potential functional polymorphisms (936C/T, 634G/C, 1612G/A, 2578C/A) of VEGFA gene in 476 HCC patients and 526 controls using matrix-assisted laser desorption ionization time-of-flight mass spectrometry method. Serum VEGF levels were measured by enzyme-linked immunosorbent assay. The Kaplan-Meier methods with log-rank test and Cox regression models were used to compare survival of resected HCC patients according to the genotype. We found that only the VEGFA 2578C/A polymorphism was significantly associated with decreased risk of HCC (AA/AC vs. CC; adjusted OR = 0.69, 95% CI = 0.51−0.93). Furthermore, the 2578C/A polymorphism was associated with significantly decreased postoperative recurrence (AA/AC vs. CC, adjusted OR = 0.51; 95% CI, 0.29−0.88) and improved overall survival (AA/AC vs. CC, adjusted HR = 0.27, 95% CI = 0.13−0.52) of resected HCC patients. In addition, the VEGF serum levels in HCC patients were significantly higher than those in healthy controls, although no significant association between VEGFA genotype and serum levels of VEGF was observed. These results suggest that the VEGFA 2578 C/A polymorphism may play a potential role in the development and clinical outcome of HCC among Chinese Han population.
Highlights
Liver cancer in men is the fifth most common cancer and the second-leading cause of cancer-related death worldwide [1]
We investigated the association of Vascular endothelial growth factor (VEGF) -936C>T, -634G>C, -1612 G/A and -2578C>A polymorphisms with susceptibility and clinical outcome of hepatocellular carcinoma (HCC) in a Chinese Han population
Our results showed that the VEGF -2578C>A polymorphism was significantly associated with HCC susceptibility among both HBsAg-positive and HBsAg- negative individuals at different ages
Summary
Liver cancer in men is the fifth most common cancer and the second-leading cause of cancer-related death worldwide [1]. The pathogenesis of HCC is not completely understood, but it is thought to be a multistage process with the complex interactions of various risk factors including infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV), cirrhosis, male gender, concurrent alcohol use, aflatoxin B1 intake and multiple genetic variants [3,4,5]. HCC is a typical hypervascular tumor, and a radiology finding of an arterial hypervascular www.impactjournals.com/oncotarget pattern is a diagnostic criterion for HCC [11].Vascular endothelial growth factor (VEGF) is a major driver of physiological and pathological angiogenesis [12]. VEGF is expressed by several tumors at higher levels than when it appears in normal tissues, and its overexpression suggests unfavorable prognosis [14, 15]. The expression levels of VEGFA mRNA in HCC was 6.95-fold higher than in HBsAg-negative healthy individuals [15]. The serum concentrations of VEGF-A have been found elevated in HCC in parallel with the tumoral grading, and they are considered independent markers of prognosis and survival [16]
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