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 p53gene in colon tumors induced by 1,2-dimethylhydrazine (DMH)in F₁ hybrid mice. Intragenic polymorphism of the p53 gene amongparental strains enabled us to assess allele loss of the p53gene and also to determine parental origin of mutated and/orlost alleles. Allele loss was detected in two of 163 tumorsheterozygous for the p53 gene. Polymerase chain reaction-single-strandconformation polymorphism analysis of p53 exons 5–8 revealed33 mutations in 20 of 182 colon tumors, the incidence beinglower than that in human colon cancers. The majority of thesemutations were of transition type: G: A transitions at non-CpGsites were most prevalent, while those at CpG sites were lesscommon. Distribution of the mutations along p53 amino acid sequencerevealed a difference in the location of ‘hot spots’between mice and humans. Incidence of p53 alterations did notdiffer among alleles of different parental origins, suggestingthat genetic changes in DMH-induced mouse colon tumors had occurredindependently of parental origin and DMH susceptibility. Detailedanalysis of p53 mutations on each allele revealed intratumoralheterogeneity in mouse colon tumors. The low incidence of p53mutations and rare allele loss suggest that p53 alteration playsonly a minor role in colon tumorigenesis in mice.