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Tumor Necrosis Factor-Alpha Gene Polymorphism Associated With Development of Hepatitis B Virus–associated Hepatocellular Carcinoma

Goal and Background: Host genetic diversity may play roles in development of HCC. This study was conducted to validate the effects of tumor necrosis factor-alpha (TNF-&agr;) gene polymorphism on development of hepatocellular carcinoma (HCC) in patients chronically infected with hepatitis B virus (HBV). Study: The study cohort comprised 224 patients with HBV-associated HCC and 206 with HBV-associated liver cirrhosis (LC). Using chromosomal DNA, TNF-&agr; promoter gene polymorphisms were determined at 3 common single-nucleotide polymorphism (SNP) sites (TNF-&agr;-1031 T>C, TNF-&agr;-857 C>T, and TNF-&agr;-308 G>A) using a single base extension method. The genotype distributions were compared between the 2 groups. All the HBV-associated LC patients were followed up regularly every 6 to 12 months for surveillance of HCC development. Results: In the cross-sectional analysis, the frequency of TNF-&agr;-857 T allele was much higher in patients with HCC compared with those with LC (42% vs. 31%, P<0.01). Of 206 HBV-associated LC patients, 12 (5.8%) developed HCC during the median follow-up period of 36 months. The cumulative occurrence rates of HCC were significantly higher in patients with TNF-&agr;-857 T allele than those withTNF-&agr;-857 C/C genotype (1-, 3-, and 5-y rates: 2.9%, 12.8%, and 20.7% vs. 0%, 3.1%, and 5.3%, respectively; P=0.013). However, the other genetic polymorphisms of TNF-&agr; promoter gene did not affect the development of HCC. In multivariate analysis, TNF-&agr;-857 T allele was a significant predictor of HCC development (hazard ratio 6.29, P=0.01). Conclusion: Our data suggest that TNF-&agr;-857 T allele is closely associated with development of HCC in HBV-associated LC patients.