Even though chronic HBV infection is associated with 80% of the cases of PHC in the world 75% of chronic carriers of HBV do not develop PHC and at least half do not develop liver disease. Little is known about the specific environmental, viral or genetic factors that affect risks of these diseases and even less is known about how these factors interact with each other. The biological basis for the hepatocarcinogenic property of HBV (and HCV) is not understood. Nor have the critical cellular and molecular genetic changes that lead to PHC been identified. To address these issues requires a multidisciplinary approach, basic studies of hepadnavirus and hepatic pathobiology, and epidemiologic studies of large populations at high risk of PHC. We plan to bring together the diverse skills of investigators at the FCCC in epidemiology and public health, biostatistics, genetics, virology, and biochemistry to conduct laboratory studies of hepadnavirus effects on hepatocellular biology and large collaborative studies of the molecular and genetic epidemiology of PHC in major endemic areas of the world (China, Senegal). Our approach is to use person-specific laboratory assays of biomarkers to understand the relationships of hepatitis virus infections (HBV, HCV, HDV), genetic events, environmental (aflatoxin-B1, iron, selenium) and other risk factors (alcohol, tobacco) to the etiology and pathogenesis of PHC, with the ultimate goal of designing new strategies to prevent PHC. The Specific Aims of the program project are: 1. In the setting of two large prospective studies in China (47,000 men) and Senegal (18,000 men), to use molecular and biochemical methods to identify viral, genetic and environmental factors associated with increased risk of developing PHC. 2. To determine whether a major susceptibility gene is responsible for clusters of PHC in certain families by use of complex segregation analysis. 3. To identify one or more human tumor suppressor genes critical to the pathogenesis of PHC by molecular genetic analysis of human tumor and non-neoplastic tissues. 4. To determine whether hepatocytes have a programmed life-span and, if so, whether infection with hepadnaviruses significantly shorten their life-span. 5. To identify the receptor(s) used by hepadnaviruses to enter hepatocytes.