Abstract
Vinyl chloride (VC) is a know animal and human carcinogen associated with liver angiosarcomas (LAS) and hepatocellular carcinomas (HCC). In VC-associated LAS mutations of the K-ras-2 gene have been reported; however, no data about the prevalence of such mutations in VC associated HCCs are available. Recent data indicate K-ras-2 mutations induce P16 methylation accompanied by inactivation of the p16 gene. The presence of K-ras-2 mutations was analysed in tissue from 18 patients with VC associated HCCs. As a control group, 20 patients with hepatocellular carcinoma due to hepatitis B (n=7), hepatitis C (n=5) and alcoholic liver cirrhosis (n=8) was used. The specific mutations were determined by direct sequencing of codon 12 and 13 of the K-ras-2 gene in carcinomatous and adjacent non-neoplastic liver tissue after microdissection. The status of p16 was evaluated by methylation-specific PCR (MSP), microsatellite analysis, DNA sequencing and immunohistochemical staining. All patients had a documented chronic quantitated exposure to VC (average 8883 ppmy, average duration: 245 months). K-ras-2 mutations were found in 6 of 18 (33%) examined VC-associated HCCs and in 3 cases of adjacent non-neoplastic liver tissue. There were 3 G → A point mutations in the tumour tissue. All 3 mutations found in non-neoplastic liver from VC-exposed patients were also G → A point mutations (codon 12- and codon 13-aspartate mutations). Hypermethylation of the 5′ CpG island of the p16 gene was found in 13 of 18 examined carcinomas (72%). Of 6 cancers with K-ras-2 mutations, 5 specimens also showed methylated p16. Within the control group, K-ras-2 mutation were found in 3 of 20 (15%) examined HCC. p16 methylation occurred in 11 out of 20 (55%) patients. K-ras-2 mutations and p16 methylation are frequent events in VC associated HCCs. We observed a K-ras-2 mutation pattern characteristic of chloroethylene oxide, a carcinogenic metabolite of VC. Our results strongly suggest that K-ras-2 mutations play an important role in the pathogenesis of VC-associated HCC. © 2001 Cancer Research Campaign
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Weihrauch, M., Benicke, M., Lehnert, G. et al. Frequent k-ras-2 mutations and p16INK4Amethylation in hepatocellular carcinomas in workers exposed to vinyl chloride. Br J Cancer 84, 982–989 (2001). https://doi.org/10.1054/bjoc.2000.1675
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DOI: https://doi.org/10.1054/bjoc.2000.1675
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