Single nucleotide polymorphism of angiogenesis-related genes associated with posthepatectomy recurrence of hepatocellular carcinoma

Abstract

BACKGROUND & AIMS: Recurrences of hepatocellular carcinoma (HCC) are very common, even after curative surgical treatment, which in turn leads to poor prognosis of the patients with HCC. Angiogenesis has been reported to have crucial roles in the growth and progression of HCC. Thus, genetic variations in angiogenesis-related genes may affect the invasiveness and recurrence of HCC. In this study, we investigated the association of single nucleotide polymorphism (SNP) of angiogenesisrelated genes with the recurrence of HCC after curative resection in patients with HCC. Methods: A total of 322 patients with HCC treated with curative resection were subjected [Age (54, 27-77; median, range), Gender (263/59; M/F), Etiology (269/17/36; HBV/HCV/NBNC)]. They were followed at 1-3 months intervals for a median period of 22 months (1-57). Recurred HCC was diagnosed histologically or clinically on the basis of the findings of CT or MRI as well as serum AFP level. Thirty-four SNP sites were selected and genotyped in angiogenesis-related genes such as vascular endothelial growth factor (VEGF), metastatic tumor antigen 1 (MTA1), hypoxia inducible factor-1A (HIF-1A), fibroblast growth factor (FGF), and insulin like growth factor-2 (IGF-2). We compared the distributions of SNPs and haplotypes in relation to the recurrence of HCC. Results: During follow-up periods, post-hepatectomy recurrence of HCC was detected in 120 patients. Recurred HCC was found more frequently in patients with a certain SNP or haplotype of FGF-2 or IGF-2 genes. The +66378 (rs1048201) T [OR 1.40 (1.01-1.94), P=0.044] and +50012 (rs6534367) G [OR 2.79 (1.13-6.86), P=0.025] alleles in FGF-2 gene were significantly associated with higher frequency of recurred HCC. In IGF-2 gene, post-hepatectomy recurrence of HCC was more frequently occurred in patients with -291 (rs3213221) C allele [OR 1.68 (1.17-2.41), P=0.005] or - 13021 (rs3741208) CT or TT genotype [OR 2.09 (1.29-3.39), P=0.003]. In haplotype analysis of IGF-2 gene, GC haplotype carriers at position +6310(rs2585)/+4702(rs3802971) showed significantly higher recurrence rate of HCC [OR 1.65 (1.15-2.38), P=0.02]. Also, at position -11228(rs2239681)/- 13021(rs3741208), CT haplotype was associated with recurrence of HCC more frequently [OR 1.88 (1.25-2.83), P=0.006], but CC haplotype carriers presented recurred HCC less frequently [OR 0.24 (0.07-0.84), P=0.049]. Conclusions: Our data indicate that single nucleotide polymorphisms in FGF- 2 and IGF-2 genes are closely associated with post-hepatectomy recurrence of HCC in patients treated with curative resection.