MUTANT C-KI-RAS P21 PROTEIN IN CHEMICAL CARCINOGENESIS IN HUMANS EXPOSED TO VINYL-CHLORIDE

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 mole cular epidemiologic biomarker with which to study this process, and wo rkers with heavy exposure to vinyl chloride (VC) represent a model pop ulation for such study. We studied the occurrence of a specific ras mu tation (Asp 13 c-Ki-ras) by oligonucleotide hybridization and the expr ession of the corresponding p21 protein in tumor tissue and serum by i mmunohistochemistry and immunoblotting with monoclonal antibodies in f ive 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 muta nt protein also was examined in nine VC-exposed workers with liver ang iomas and 45 VC-exposed workers with no evidence of liver neoplasia; e ight of nine (89 percent) of the former and 22 of 45 (49 percent) of t he latter were also positive for the mutant p21 in their serum. Howeve r, serum immunoblotting results for 28 age-gender-race matched, unexpo sed 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. The se results suggest that detection of serum mutant p21 protein can be a valid surrogate for ras gene expression at the tissue level. Further, serum mutant p21 may be a useful molecular epidemiologic biomarker fo r the study of chemical carcinogenesis in humans exposed to VC and pos sibly for the study of other mutant ras-related human cancers.