The interaction and mechanisms of the major risk factors for human hepatocellular carcinoma (HCC) will be analyzed in an animal model. World- wide HCC is arguable the tumor that causes the highest cancer mortality. HCCs occurring in high-risk areas of the world are associated with hepatitis B(HBV) infection and aflatoxin (AFB1) exposure, and these tumors have a high frequency of mutations in the tumor suppressor gene p53 at codon 249 (p53ser249). In specific Aim 1, the effect of expression of p53, HBV injury and AFB1 exposure on development of pre-neoplastic lesions and HCC development will be studied using F1s of p53 null mice X HBsAg transgenic lineage 50-4 mice. In specific aim 2, the effect of p53 mutation will be determined using a newly established mutant p53ser246 (equivalent to human p53ser249) mouse lineage. In specific aim 3 the mechanisms for effects of loss on p53, p53 mutation and AFB1 exposure on hepatocyte proliferation during carcinogenesis will be examined by analysis of specific cell cycle events and expression or reactivity to liver growth factors. In specific aim 4 HCCs arising in this model will be tested for chromosomal changes and cell cycle alterations and related to those in pre-neoplastic livers. These studies should lead to an understanding of how each of these risk factors affect hepatocyte proliferation and how these effects contribute to AFB1 hepatocarcinogenesis.