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Mutagenesis of the H-ras Protooncogene and the p53 Tumor Suppressor Gene¹

Department of Carcinogenesis, Swiss Institute for Experimental Cancer Research, Ch. Boveresses 155, 1066 Epalinges/Lausanne, Switzerland

Point mutations in ras protooncogenes and in the p53 tumor suppressor gene are common in many forms of human cancer. The identification of carcinogens which are responsible for their induction in humans is of great interest because it may suggest measures for disease prevention. Furthermore, the load of somatic mutations in cancer-related genes in premalignant tissues may become a useful parameter for risk assessment. For the measurement of such mutations, highly sensitive genotypic mutation systems are required which avoid the selection and clonal expansion of cells on the basis of a mutated phenotype.

We have developed the restriction fragment length polymorphism/polymerase chain reaction method for genotypic mutation analysis and applied it to the study of the mutability of hot-spot codons in c-H-ras1 and p53 genes with human carcinogens. In particular, we studied the mutability of codons 247–250 of p53 with the mycotoxin aflatoxin B₁ (AFB₁) in human hepatocytes. AFB₁ preferentially induced the transversion of guanosine to thymidine in the third position of codon 249, generating the same mutation which is found in a large fraction of hepatocellular carcinomas from regions of the world with AFB₁-contaminated food. Our results are in support of AFB₁ as an etiological factor for hepatocellular carcinoma in AFB₁-contaminated areas.

In an ongoing study we are comparing the load of mutations in hot-spot codon 12 of c-H-ras1 in urinary bladder carcinoma and in normal tissue, by restriction fragment length polymorphism/polymerase chain reaction. We observed moderately elevated abundances of guanosine to thymidine transversions in the middle position of codon 12 in tumor DNA. These results may reflect a mutator phenotype of the tumor tissue or they could be the consequence of the heterogeneity of the biopsies which were analyzed.