Investigation of Hepatitis B Virus Chromosomal Integration Sites and the Integrated Truncated S Gene Mutants in Association with Postoperative Prognosis in Hepatocellular Carcinoma

In Taiwan, hepatocellular carcinoma (HCC) ranks the second common cause of cancer-related death. Despite a successful vaccination program, hepatitis B virus (HBV) remains the major etiological factor for HCC in patients older than 25 years of age. Our Lab recently discovered that high intrahepatic HBV-DNA levels and BCP A1762T/G1764A mutation in liver tissue independently predicted postoperative survival in HCC (Yeh el al. Hepatology 2010). Accordingly, an independent, subsequent study discovered that the mutant HBx protein caused by the overlapping BCP mutations contributed to hepatocarcinogenesis (Gastroenterology 2011; Lok AS’s group). Such study experiences strongly suggested that investigation of the postoperative prognostic molecular factors very likely led to important clues for the key oncogenic pathways in HCC. On the other hands, our groups have shown that potent anti-HBV treatment frequently leads to selection of the S gene mutants (Hsu and Yeh, Hepatology 2011; Gastroenterology 2007). Additionally, many previous studies indicated that the S gene stop codon mutations were frequently found in the integrated HBV genomes. Encouraged by these interesting findings, in this proposal, we aim to investigate the predictive value of genetic factors including HBV integration patterns and sites and the S gene truncation mutations in association with the postoperative survivals in HBV-associated HCC. Two groups of patients will be investigated and the molecular mechanisms of hepatocarcinogenesis will be studied using an established transgenic mice model carrying a truncated S gene in the following 3 years: 1. Patients with HBV-associated HCC following surgical resection. Virological factors in liver tissues were found to predict postoperative survival in our recently publication (Hepatology 2010). As a second step, we will examine the survival predictive value of HBV integration patterns and sites. Our preliminary data showed that HBV integration in one specific orientation is associated with postoperative disease-free survival (see preliminary data). Furthermore, an integration hot spot was accidentally found in patients with early postoperative recurrence (see preliminary data). In this proposal, we will verify these data. On the other hand, we will examine whether the integrated truncated S gene mutants is associated with postoperative prognosis. 2. Patients with HBV-associated HCC following liver transplantation. After liver transplantation, HCC could relapse. In these patients, the effect of host immunity was markedly suppressed by immune suppressants. Thus, we are able to investigate the direct role of HBV in hepatocarcinogenesis without interference of host immunity. Virological factors including HBV-DNA level, precore stop codon mutation, basal core promoter mutation, genotype, and pre-S/S mutation will be determined. These virological factors together with clinical parameters will be used to correlate with clinical prognosis. Additionally, the aforementioned HBV integration patterns and sites and the S gene truncation mutations will also be assessed for their prognostic value. 3. A line of transgenic mice carrying the sW172* mutation has been established together with a line carrying the wild type S gene. We wish to continue this study by observing the difference of HCC incidence. Additionally, clues of the molecular mechanisms for HCC oncogenesis will be searched. In summary, this study can lead to further understanding for HBV-related hepatocarcinogenesis. Survival analysis may lead to new tools for clinical application.

Project ID:PC10301-1151
External Project ID:NSC101-2314-B182-017-MY3