Mutant c-Ki-ras p21 protein in chemical carcinogenesis in humans exposed to vinyl chloride

Abstract

Mutations in ras oncogenes and expression of their encoded p21 protein products are believed to play an important role in carcinogenesis in humans. Detection of mutant p21 proteins in serum may be a useful molecular epidemiologic biomarker with which to study this process, and workers with heavy exposure to vinyl chloride (VC) represent a model population for such study. We studied the occurrence of a specific ras mutation (Asp 13 c-Ki-ras) by oligonucleotide hybridization and the expression of the corresponding p21 protein in tumor tissue and serum by immunohistochemistry and immunoblotting with monoclonal antibodies in five individuals with heavy exposure to VC and resultant angiosarcomas of the liver (ASL). Four of five (80 percent) of the cases of ASL were found to contain the mutation and to express the corresponding mutant protein in their tumor tissue and serum. Serum expression of the mutant protein also was examined in nine VC-exposed workers with liver angiomas and 45 VC-exposed workers with no evidence of liver neoplasia; eight of nine (89 percent) of the former and 22 of 45 (49 percent) of the latter were also positive for the mutant p21 in their serum. However, serum immunoblotting results for 28 age-gender-race matched, unexposed controls were all negative. Stratification by years of VC exposure showed a significant linear trend (P < 10(-5)) for the occurrence of the serum mutant p21 protein with increasing duration of exposure. These results suggest that detection of serum mutant p21 protein can be a valid surrogate for ras gene expression at the tissue level.(ABSTRACT TRUNCATED AT 250 WORDS)

Non-infective occupational risk factors for hepatocellular carcinoma: A review

“…In addition, in VCM-exposed workers with HCC, a high prevalence of Kirsten rat sarcoma viral oncogene homolog (KRAS)2 mutations (58) and a characteristic p53 mutation pattern (58) have been identified. In ASL, a distinctive GGC to GAC mutation is observed in the KRAS2 gene at codon 13, or less often at codon 12, where it is also G to A (148,149). The p53 gene mutations that are observed in VCM-induced ASL occur at multiple positions on the p53 gene and do not appear to be characteristic of VCM exposure (56,150).…”

Vinyl chloride and the liver

“…Mutations of Ki-ras-2 and p53 genes have been described in ASL; although it has been suggested that some of these mutations may be characteristic of VCM exposure, the same mutations have also been reported in other tumors and in other ASL, in absence of any exposure to VCM [13][14][15][16][17]. There is a characteristic mutation in the Kiras-2 gene at codon 13 (GGC to GAC), or less commonly at codon 12 (also G to A) [13,14]. The mutations in the p53 gene that are found in VCM-induced ASL occur in several different positions on the p53 gene and do not appear to be characteristic for vinyl chloride exposure [15,16].…”

“…This would obviously be important to document as an important piece of evidence as to whether VCM exposure could lead to HCC. Although mutations in liver tissue have not been investigated mutated Ki-ras and p53 proteins have been discovered in the blood of workers exposed to VCM [14,[17][18][19][20]. In particular a doseresponse relationship was present between level of exposure to VCM and likelihood of finding the mutated protein in blood.…”

Cancer epidemiology: study designs and data analysis

“…DDT and DDE concentrations were significantly higher among K-ras mutated cases than among K-ras wild-type [27]. Other examples consider the Nras mutations and occupational exposures in patients with acute myeloid leukaemia [28], to K-ras mutations and asbestos exposure in lung adenocarcinoma [29], and to K-ras p21 protein and vinyl chloride exposure in angiosarcomas of the liver [30]. A more recent example studied different dietary characteristics -as exposure factors-in relation to colorectal adenomas [31].…”