title: Mutation analysis of K-ras-2 in liver angiosarcoma and adjacent nonneoplastic liver tissue from patients occupationally exposed to vinyl chloride.
abstract: Vinyl chloride (VC) is a potent liver carcinogen that induces angiosarcomas in humans and animals. Recent evidence shows that liver tumors from patients with VC exposure may have a specific K-ras mutation pattern. This study was performed to determine the status of K-ras-2 in liver angiosarcomas (LAS) from workers occupationally exposed to VC. We examined the presence of K-ras-2 mutations in 15 LAS from patients with known exposure to VC (median exposure: 8,260 ppm [range 3,900- 21,000 ppm]]. In all cases, other risk factors for the development of LAS were excluded. Direct DNA sequencing after microdissection of the tumor cells was used for the analysis. Heterozygous mutations of K-ras-2 were detected in 8/15 LAS (53%). Five patients (33%) had a mutation of codon 12 and three of codon 13 (20%). The most common changes were G-->A transitions in five LAS which lead to the substitution of aspartic acid for glycine in the resulting p21 protein. In two patients (13%), mutations of the K-ras-2 gene were identified in the adjacent nonneoplastic liver tissue. These data indicate that VC induces a high frequency of G-->A transitions in human LAS. This mutation pattern is likely a consequence of VC-DNA-adduct formation.
authors.affiliation: Institute of Occupational Medicine, University of Hannover, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Weihrauch
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.forename: Gerhard
authors.initials: G
authors.lastname: Lehnert
authors.forename: Bernd
authors.initials: B
authors.lastname: Koch
authors.forename: Christian
authors.initials: C
authors.lastname: Wittekind
authors.forename: Renate
authors.initials: R
authors.lastname: Wrbitzky
authors.forename: Andrea
authors.initials: A
authors.lastname: Tannapfel
mesh_terms: D000368:Aged; D001483:Base Sequence; D017931:DNA Primers; D005260:Female; D011905:Genes, ras; D006394:Hemangiosarcoma / Q000139:chemically induced / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism*; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016273:Occupational Exposure; D014752:Vinyl Chloride / Q000009:adverse effects*
chemical_list: D017931:DNA Primers; D014752:Vinyl Chloride