| Liver cancer, specifically hepatocellular carcinoma (HCC), has been identified as the fourth most common cancer to cause mortality worldwide. Viral hepatitis infection is a major risk factor for HCC development and in geographic regions of high HCC incidence, the primary causes of the disease are exposure to dietary aflatoxins and infection with hepatitis B virus (HBV). Various single nucleotide hotspot mutations that are thought to be acquired within host-integrated HBV DNA have been observed, including a double mutation in the X gene at nucleotide positions 1762 and 1764 and a mutation in the pre-core region at nucleotide 1896. Epidemiologic studies have shown that the presence of these HBV hotspot mutations in serum DNA puts individuals at increased risk for the development of HCC compared to those individuals that do not harbor the mutations. It is unclear what factors in addition to chronic HBV infection are necessary for HCC development, but it is likely that these hotspot mutations are involved.;The studies presented in this dissertation focus on these HBV hotspot mutations in several capacities: characterization of the relationship between wild-type and mutant HBV X proteins with p53, as well as the biology of mutation formation in both cellular and animal models, and qualitative detection of the HBV 1896 mutation in human serum DNA by mass spectrometry. The research done for this dissertation revealed that both wild-type and mutant HBV X proteins physically interact with p53 protein, but unlike the wild-type protein, the mutant HBV X protein inhibits both p53-mediated gene transcription and cell growth in a p53-proficient cell line. The differences in activity between wild-type and mutant HBV X protein could start to explain the epidemiologic importance of this particular hotspot mutation. Important follow-up studies are suggested in this dissertation. The challenges present in examining hotspot mutation acquisition in HBV cell and animal models are also described. A qualitative method for identifying the presence of the HBV 1896 mutation in human serum DNA is presented as well. |
