FUNCTIONAL INACTIVATION BUT NOT STRUCTURAL MUTATION OF P53 CAUSES LIVER-CANCER

Structural mutations in the p53 gene are seen in virtually every form of human cancer. To determine whether such mutations are important for initiating tumorigenesis, we have been studying hepatocellular carcin oma, in which most cases are associated with chronic hepatitis B virus infections. Using a transgenic mouse model where expression of a sing le HBV gene product, the HBx protein, induces progressive changes in t he liver, we show that tumour development correlates precisely with p5 3 binding to HBx in the cytoplasm and complete blockage of p53 entry i nto the nucleus. Analysis of tumour cell DNA shows no evidence for p53 mutation, except in advanced tumours where a small proportion of cell s may have acquired specific base substitutions. Our results suggest t hat genetic changes in p53 are late events which may contribute to tum our progression.