P53 GENE MUTATION PATTERN IN RAT-LIVER TUMORS INDUCED BY VINYL-CHLORIDE

Vinyl chloride (VC) induces angiosarcomas of the liver (ASL) and hepat ocellular carcinomas (HCCs) in humans and rodents. We examined the pre sence of p53 gene mutations in ASL and BCC induced by VC in Sprague Da wley rats; 25 ASL and eight HCCs were analyzed for point mutations in exons 5-8, using PCR amplification, single-strand conformation polymor phism analysis, and direct DNA sequencing. Mutations were found in 11 (44%) of the ASL and in 1 HCC. A 12-base pair deletion was found in on e tumor; all others were base pair substitutions. Nine of the point mu tations were observed at A:T base pairs (5 A:T --> T:A; 2 A:T --> G:C, and 2 A:T --> C:G), and of three G:C --> A:T transitions, only one wa s at a CpG site. In ASL, four mutations were found in exon 5, two in e xon 6, and six in exon 7; the base pair substitution found in one HCC was in exon 8. One ASL exhibited two point mutations, including a sile nt one. Two ASL exhibited the same mutation in codon 203 and two other samples in codon 253. Codon 235 was found to be mutated in three ASL. These data show that p53 is often mutated in ASL induced by VC in rat s and, as observed in ASL in humans exposed to VC, the majority of the missense mutations involved A:T base pairs. The characteristic patter ns of mutations found suggest that a common mechanism operates in VC-i nduced p53 mutagenesis in both species, and these mutations are consis tent with the formation of DNA etheno adducts by VC in the liver. The A:T --> T:A transversion observed in the first nucleotide of codon 253 in two rat ASL is equivalent to the A:T --> T:A transversion characte rized previously in codon 255 in one human ASL associated with VC expo sure.