P53 GENE ABNORMALITIES ARE CLOSELY-RELATED TO HEPATOVIRAL INFECTIONS AND OCCUR AT A LATE-STAGE OF HEPATOCARCINOGENESIS

Hepatocellular carcinoma (HCC) accumulates a mutation of the p53 gene with a common substitution of nucleotide in a particular site. It is h ypothesized that infection of hepatitis B virus (HBV) or exposure to a flatoxins could induce it. In Japan, the concentration of aflatoxins i n the environment is low; however, infection of HBV and/or hepatitis C virus (HCV) is frequently seen in patients with HCC. The purpose of o ur studies was to determine whether these hepatoviral factors influenc e p53 alterations. In our results, p53 abnormalities, which were compo sed of loss of heterozygosity (LOH) and/or point mutation, were shown in 39% of patients. We postulated that they occurred at late stages in tumor growth based on the following two results. LOH analysis on p53 showed that most of the tumor nodule consisted of two phenotypes, LOH and non-LOH cancer cells. The p53 abnormalities correlated with the gr ade of cancer cell atypia which advanced with tumor growth. HBV and HC V infections were identified by polymerase chain reaction using DNA ex tracted from cancerous and noncancerous regions of the liver. By these methods, the patients who had been infected with either HBV or HCV sh owed an incidence of p53 abnormalities (45%) higher than those infecte d by neither (13%). However, the detection rate of these viruses was l ower in the HCC region (33%) than that in the noncancerous region (56% ) in cases with mutated p53. The low rate of HCV detection (22%) in th e HCC region with altered p53 was attributable to these different vira l detection rates. There was a difference in pattern of p53 mutational changes in patients depending upon whether they were infected by HBV or by HCV. Two of three HBV-infected patients had a transversional cha nge of nucleotide at the G:C site to T.A. However, in cases with HCV, four of eight patients had a transitional change of nucleotide of p53. These results showed that HBV and HCV infections affect carcinogenic pathways causing p53 abnormalities independently.