P53 mutation pattern in hepatocellular carcinoma in workers exposed to vinyl chloride

Abstract

Vinyl chloride (VC) is a known animal and human carcinogen that is associated with liver angiosarcoma and most likely also with hepatocellular carcinoma (HCC) in humans. The authors examined the presence of p53 gene mutations in 18 HCC specimens from patients with known exposure to VC (median, 8883 parts per million-years; median duration, 245 months). In all cases, other risk factors for the development of HCC (hepatitis B virus and hepatitis C virus infections, alcohol consumption, and metabolic or autoimmune disorders) were excluded. Three patients had concomitant cirrhosis. The p53 gene was examined by direct sequencing of exons 5-9. Mutations of the p53 gene were found in 11 of 18 HCCs examined. The point mutations detected were comprised of five transversions and five transitions. Five of 11 mutations (codons 175, 245, 248, 273, and 282) occurred at CpG sites. Histopathologic liver alterations (mild sinusoidal dilatation, [portal] fibrosis, and centrilobular siderosis) in tumor surrounding nonneoplastic liver confirmed exposure to VC. The results of the current study indicated a relation between VC exposure and the development of HCC. The mutation pattern of p53 with a nearly equal rate of incidence of transitions and transversions and a high rate of incidence of mutations at CpG sites may reflect endogenous mechanisms (e.g., deamination of 5-methylcytosine) rather than exogenous carcinogens.