Influence of hepatitis B virus core promoter mutations on hepatocellular carcinoma among Japanese patients

在3个独立的研究中评估了各亚型之间增强子II/核心启动子和前C区的病毒差异及其与肝细胞癌（HCC）的相关性：1）118例HBV/C1/Cs和210例HBV/C2/Ce携带者的匹配横断面对照研究; 2）8例IC和8例HCC患者血清转换前后感染HBV基因型C的对照研究; 3）一项年龄、性别和HBeAg状态匹配的横断面对照研究，在80名日本HBV/C2感染的HCC患者和80名非HCC患者之间进行。我们的数据表明，T1653和/或V1753突变除了T1762/A1764是强相关的背景下，HBeAg状态的HBV/C-携带者的HCC。HBV/C基因型具有特异性的突变模式，这可能是导致HBV/C2/Ce致癌性增加的原因。不同基因型的HBV可引起不同严重程度的肝病，但其潜在的病毒学差异尚不清楚。Huh 7细胞用携带1.24倍不同基因型/亚型HBV基因组的质粒转染（Aa/A1、Ae/A2、Ba/B2和D各2株; Bj/B1和C各3株）。用人肝细胞的uPA/SCID小鼠接种从培养物上清液中回收的病毒体的小鼠传代。在接种后4-7周内，C组小鼠的血清HBV DNA水平比Ae组高2个对数。总之，HBV基因型之间的病毒学差异在组织培养和嵌合小鼠中均得到证实。这些差异可能会影响不同基因型的HBV感染在临床和流行病学设置。

Viral differences in enhancer II/core promoter and precore regions between the subgenotypes and their association with hepatocellular carcinoma (HCC) were assessed in 3 independent studies; 1)a matched cross-sectional control study of 118 carriers with HBV/C1/Cs and 210 HBV/C2/Ce; 2) a control study among 8 IC and 8 HCC patients infected with HBV genotype C before and after seroconversion; 3)an age, sex, and HBeAg status matched cross-sectional control study between 80 Japanese patients infected with HBV/C2 with HCC and 80 without HCC. Our data indicate that T1653 and/or V1753 mutations in addition to T1762/A1764 are strongly associated with HCC in context of HBeAg status among HBV/C-carriers. HBV/C subgenotypes have specific mutation patterns, which is probably responsible for increased carcinogenesis of HBV/C2/Ce.HBV of various genotypes may induce liver disease of distinct severity, but the underlying virological differences are not well defined. Huh7 cells were transfected with plasmids carrying 1.24-fold the HBV genome of different genotypes/subgenotypes (2 strains each for Aa/A1, Ae/A2, Ba/B2 and D; 3 each for Bj/B1 and C). uPA/SCID mice with human hepatocytes were inoculated with mouse passages of virions recovered from culture supernatants. Serum levels of HBV DNA in these mice were higher for C than Ae by 2 logs during 4-7 weeks post-inoculation. In conclusion, virological differences among HBV genotypes were demonstrated both in tissue culture and chimeric mice. These differences may influence HBV infections with distinct genotypes in clinical and epidemiological settings.