ras gene mutations in vinyl chloride-induced liver tumours are carcinogen-specific but vary with cell type and species

Abstract

Previous studies have shown that a high proportion (5/6) of human liver angiosarcomas (ASL) associated with exposure to vinyl chloride (VC) contains a GC=AT mutation at the Ki-ras codon 13. This mutation, however, has not been found in 5 ASL or 2 hepatocellular carcinomas (HCC) induced in rats by VC. These 2 HCC did contain a mutation at codon 61 of the Ha-ras gene. In order to extend this study and further explore the mechanisms of tumour induction, an additional 6 ASL and 6 HCC induced in rats by VC were analysed for ras gene point mutations, as well as 10 rat and 10 murine ASL induced by vinyl fluoride (VF), and 5 ASL, 6 Kupffer cell sarcomas, 4 HCC and 2 cholangiocellular carcinomas induced by Thorotrast in rats. Tumour DNA was analysed by PCR-SSCP and direct sequencing. None of the rodent ASL contained a mutation at codon 13 of the Ki-ras gene showing that the ras gene mutational pattern is species-specific. The CAA=CTA mutation, previously found at codon 61 of the Ha-ras gene in rat HCC, was observed in 5 further VC-induced HCC but was not detected in the Thorotrast-induced HCC, suggesting carcinogen-specificity. This mutation was also absent in VC-induced ASL, which supports the cell-specificity of the ras mutational pattern in chemically induced tumours. No predominant mutation was detected in VF-and Thorotrast-induced tumours. Thus, a given mutation in a tumour may be carcinogen-specific but also depend on the species and the cell type. Int.

High prevalence of K- ras -2 mutations in hepatocellular carcinomas in workers exposed to vinyl chloride

“…This supports the data from K-ras-2 mutation studies in LASs of VC-exposed workers, where 83% of the tumours were found to contain G ® A point mutations at codon 13. Exposure to VC produced a similar mutation pattern with G: C ® A:T point mutations at codon 61 of the N-ras gene in liver tumours in Sprague-Dawley rats (Froment et al 1994;Boivin-Angele et al 2000). Within our control group of sporadic HCCs, the mutations were G ® T, and G ® A changes without any predominance of base pairs aected.…”

“…K-ras-2 oncogene mutations are frequently found in chemically induced HCCs in experimental animals (Boivin-Angele et al 2000;Xia et al 1998;Chao et al 1999), in contrast, the frequency of K-ras-2 mutations in human HCCs is much less (Tada et al 1990;Challen et al 1992;Leon and Kew 1995). To date, there are few studies on the prevalence of ras mutations in sporadic HCCs of various aetiologies.…”

“…Recent studies demonstrate mutation analysis of the oncogene K-ras-2 analysed in human LAS associated with VC (DeVivo et al 1994;Luo et al 1998) and in animal models (Soman and Wogan 1993;Froment et al 1994;Barbin et al 1997;Boivin-Angele et al 2000), yet no published data for human HCC due to VC have been presented. To analyse the K-ras-2 oncogene we examined tissue from 12 patients with resected HCCs and known high chronic VC exposure.…”

Mutation analysis of K‐ras‐2 in liver angiosarcoma and adjacent nonneoplastic liver tissue from patients occupationally exposed to vinyl chloride

“…In our study, 8 of 15 cases (53%) of LAS exhibited a mutation in the K-ras-2 gene, with five G3 A point mutations of codon 12 and 13. Exposure of Sprague-Dawley rats to VC produced liver tumors, with a similar mutation pattern with G:C3 A:T point mutations at codon 61 of the N-ras gene [Fromment et al, 1994;Boivin-Angele et al, 2000]. Collectively, these observations suggest that VC induces a high frequency of G:C3 A:T point mutations.…”

Carcinogenicity and Mechanistic Insights on the Behavior of Epoxides and Epoxide‐Forming Chemicals

“…mutations (G → A transitions) in workers exposed to vinyl chloride 35,36 and H-ras mutations (A → T transversions) in vinyl chloride-exposed rats. 37 K-ras and p53 mutations have also been detected in hemangiosarcomas induced by 1,3-butadiene in mice. 38 In addition, K-ras mutations were observed in lung carcinomas and in harderian gland carcinomas in mice exposed to 1,3-butadiene, chloroprene, or isoprene.…”