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p53 Gene Mutation Pattern in Rat Liver Tumors Induced by Vinyl Chloride¹

IARC, 150, Cours Albert Thomas, 69372 Lyon Cedex 08, France [A. B., O. F., R. M.]; Institut National de la Santé et de la Recherche Médicale, Unité 271, 151, Cours Albert Thomas, 69424 Lyon Cedex 03, France [S. B., M-J. M.], and Cancer Research Center, European Ramazzini Foundation of Oncology and Environmental Sciences, Castle of Bentivoglio, 40010 Bentivoglio Bologna, Italy [F. B., C. M.]

Vinyl chloride (VC) induces angiosarcomas of the liver (ASL) and hepatocellular carcinomas (HCCs) in humans and rodents. We examined the presence of p53 gene mutations in ASL and HCC induced by VC in Sprague Dawley rats; 25 ASL and eight HCCs were analyzed for point mutations in exons 5–8, using PCR amplification, single-strand conformation polymorphism 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 one tumor; all others were base pair substitutions. Nine of the point mutations 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 was at a CpG site. In ASL, four mutations were found in exon 5, two in exon 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 silent 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 rats and, as observed in ASL in humans exposed to VC, the majority of the missense mutations involved A:T base pairs. The characteristic patterns of mutations found suggest that a common mechanism operates in VC-induced p53 mutagenesis in both species, and these mutations are consistent 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 characterized previously in codon 255 in one human ASL associated with VC exposure.

¹ This work was supported in part by National Institute of Environmental Health Sciences Grant ES 05948 (to A. B.) and by Grant EV5V-CT920199 (to R. M.) from the European Commission.

² To whom requests for reprints should be addressed.

³ Present address: Institut de Pathologie et de Génétique, 41, Allée des Templiers, 6280 Gerpinnes (Loverval), Belgium.

Received 11/26/96. Accepted 3/10/97.

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