Mutational and LOH analyses of p53 alleles in colon tumors induced by 1,2-dimethylhydrazine in F1 hybrid mice.

To elucidate the role of p53 in colon tumorigenesis in mice, we examined allele loss and mutational alteration of the p53 gene in colon tumors induced by 1,2-dimethylhydrazine (DMH) in F1 hybrid mice. Intragenic polymorphism of the p53 gene among parental strains enabled us to assess allele loss of the p53 gene and also to determine parental origin of mutated and/or lost alleles. Allele loss was detected in two of 163 tumors heterozygous for the p53 gene. Polymerase chain reaction-single-strand conformation polymorphism analysis of p53 exons 5-8 revealed 33 mutations in 20 of 182 colon tumors, the incidence being lower than that in human colon cancers. The majority of these mutations were of transition type: G:A transitions at non-CpG sites were most prevalent, while those at CpG sites were less common. Distribution of the mutations along p53 amino acid sequence revealed a difference in the location of 'hot spots' between mice and humans. Incidence of p53 alterations did not differ among alleles of different parental origins, suggesting that genetic changes in DMH-induced mouse colon tumors had occurred independently of parental origin and DMH susceptibility. Detailed analysis of p53 mutations on each allele revealed intratumoral heterogeneity in mouse colon tumors. The low incidence of p53 mutations and rare allele loss suggest that p53 alteration plays only a minor role in colon tumorigenesis in mice.