The p53 signaling pathway works as a potent barrier to tumor progression. Two single nucleotide polymorphisms (SNPs) in the gene loci of p53 pathway, p53 codon 72 Arg72Pro and MDM2 SNP309 (T > G), have been shown to cause perturbation of p53 function, but the effect of the two SNPs on the risk of hepatocellular carcinoma (HCC) remains inconsistent. This study investigated the influence of combined p53 Arg72Pro and MDM2 SNP309 on the risk of developing HCC in patients with chronic hepatitis B virus infection, and evaluated the significance of the two combined SNPs on patient prognosis. In total, 350 HCC patients, 230 non-HCC patients, and 96 healthy controls were genotyped for the p53 Arg72Pro and MDM2 SNP309. The combined p53 Pro/Pro and MDM2 G/G genotype was significantly associated with HCC risk (P = 0.047). Multivariate analysis indicated that combined p53 Pro/Pro and MDM2 G/G genotype was an independent factor affecting recurrence and survival (P < 0.05). Patients with combined p53 Pro/Pro and MDM2 G/G genotypes had a poorer prognosis than other genotypes, P < 0.01 for both disease-free survival (DFS) and overall survival (OS). DFS and OS rates also differed significantly between Barcelona Clinic Liver Cancer (BCLC) stage A patients with combined p53 Pro/Pro and MDM2 G/G and other genotypes (P < 0.05). Thus, the combined p53 Pro/Pro and MDM2 G/G genotype is associated with increased risk of developing HCC and is an independent adverse prognostic indicator in early stage HCC.
Carcinoma, Hepatocellular ; diagnosis ; genetics ; surgery ; virology ; Carrier State ; virology ; Cohort Studies ; Female ; Genetic Predisposition to Disease ; genetics ; Hepatitis B virus ; physiology ; Humans ; Liver Neoplasms ; diagnosis ; genetics ; surgery ; virology ; Male ; Middle Aged ; Neoplasm Staging ; Polymorphism, Single Nucleotide ; Prognosis ; Proto-Oncogene Proteins c-mdm2 ; genetics ; Tumor Suppressor Protein p53 ; genetics

BACKGROUND/AIMS: Human hepatocellular carcinoma (HCC) is a hypervascular tumor, and vascular endothelial growth factor (VEGF) plays a key role in the regulation of tumor-associated angiogenesis. In this study, we analyzed the significance of the expression of VEGF family members on the prognosis and clinicopathologic progress of HCC. METHODS: Surgically resected specimens of HCC and noncancerous liver tissue were obtained from 323 patients with HCC, and VEGF mRNA was examined by quantitative reverse transcriptase-polymerase chain reactions (RT-PCRs). Patients who were seropositive for hepatitis B surface antigen were selected for the analysis (n=208). The VEGF(tumor)/GAPDH (glyceraldehyde-3-phosphate dehydrogenase)(tumor)/VEGF(nontumor)/GAPDH(nontumor) ratio was calculated using a quantitative RT-PCR assay, and the relationships between the expressions of VEGF family members and clinicopathologic parameters were analyzed to evaluate their significance in the prognosis of HCC. RESULTS: The disease-free survival was significantly worse in the high-VEGF-A group than in the low-VEGF-A group (P=0.035), whereas VEGF-A expression was not significantly related to overall survival (P=0.172). The factors significantly related to poor prognosis in univariate analysis were tumor size, portal vein invasion, microvascular thrombi, intrahepatic metastasis, tumor capsule invasion, liver capsule invasion, preoperative serum albumin level, and VEGF-A ratio. Multivariate analysis showed that a poor prognosis in HCC patients was significantly related to portal vein invasion (hazard ratio=3.381, P<0.001), intrahepatic metastasis (hazard ratio=2.379, P<0.001), tumor size (hazard ratio=1.834, P=0.003), and preoperative serum albumin level (hazard ratio=2.050, P=0.006). CONCLUSIONS: Our study showed that the expression of VEGF-A is positively correlated with the recurrence rate of HCC after curative resection. Therefore, a high expression of VEGF-A might be predictive of HCC recurrence after curative resection.
Adult ; Aged ; Base Sequence ; Carcinoma, Hepatocellular/*diagnosis/*surgery/virology ; Female ; Hepatitis B/complications ; Hepatitis B Surface Antigens/blood ; Humans ; Liver Neoplasms/*diagnosis/*surgery/virology ; Male ; Middle Aged ; Molecular Sequence Data ; Multivariate Analysis ; Neoplasm Invasiveness ; Neoplasm Staging ; Predictive Value of Tests ; Prognosis ; RNA, Messenger/analysis ; Reverse Transcriptase Polymerase Chain Reaction ; Survival Analysis ; Vascular Endothelial Growth Factors/genetics/*metabolism