Mutations in the p53 tumor suppressor gene in tree shrew hepatocellular carcinoma associated with hepatitis B virus infection and intake of aflatoxinB1

Infection with hepadnaviruses and exposure to aflatoxin B1 (AFB1) are consi dered to be major risk factors in the development of hepatocellular carcino ma (HCC) in humans. A high rate of p53 mutations at codon 249 has been repo rted in these tumors. The tree shrew (Tupaia belangeri chinensis) is a usef ul animal model for the development of HCC after human hepatitis B virus (H BV) infection or AFB1 treatment. Therefore, it was of particular interest t o determine whether the p53 gene in tree shrew HCCs associated with HBV inf ection and/or with exposure to AFB1 is affected in the same manner as in hu man HCCs. We determined the tree shrew p53 wild-type nucleotide sequences b y RT-PCR and automatic DNA-sequencing. Tree shrew wild-type p53 sequence sh owed 91.7 and 93.4% homologies with human p53 nucleotide and amino acids se quences, respectively, while it showed 77.2 and 73.7% homologies in mice. O ne HCC and normal liver tissue from AFB1 treated and one HCC from AFB1- and HBV-treated tree shrew showed no change in p53 sequences, while three HCCs from AFB1- and HBV-treated tree shrews showed point mutations in p53 seque nces. One HCC showed point mutations at codon 275, which is on the DNA-bind ing domain of p53 gene, which might be a cause of gain-of-function during t he development of HCC. As a result, our finding indicates that tree shrews exposed to AFB1 and/or HBV had neither codon 249 mutations nor significant levels of other mutations in the p53 gene, as is the case with humans. (C) 2000 Elsevier Science B.V. All rights reserved.