TP53 and liver carcinogenesis

Abstract

Primary hepatocellular carcinoma (HCC) is one of the most common malignancies and has the fourth highest mortality rate worldwide. The major risk factors, including chronic infections with the hepatitis B or C virus, are exposure to dietary aflatoxin B₁(AFB₁), vinyl chloride, or alcohol consumption. Southern China and sub‐Saharan Africa have the highest dietary AFB₁ exposure, making it and hepatitis B virus (HBV) the major causes of cancer mortality in these geographic areas. Recent studies have discovered genetic and epigenetic changes involved in the molecular pathogenesis of HCC, including somatic mutations in the p53 tumor suppressor gene (TP53). AFB₁ induces typical G:C to T:A transversions at the third base in codon 249 of p53. Chronic active hepatitis B and C (HCV) infection, and further inflammatory and oxyradical disorders including Wilson disease (WD) or hemochromatosis, generate reactive oxygen/nitrogen species that can damage DNA and mutate the p53 gene. The X gene of HBV (HBx) is the most common open reading frame integrated into the host genome in HCC. The integrated HBx is frequently mutated and has a diminished ability to function as a transcriptional cotransactivator and to activate the NF‐kappa B pathway. However, the mutant HBx proteins still retain their ability to bind to and abrogate p53‐mediated apoptosis. In summary, both viruses and chemicals are implicated in the etiology and molecular pathogenesis of HCC. The resultant molecular changes in the ras and Wnt signal‐transduction pathways, and the p53 and Rb tumor suppressor pathways significantly contribute to liver carcinogenesis. Hum Mutat 21:201–216, 2003. Published 2003 Wiley‐Liss, Inc.