Genetic instability and p53 mutations in metastatic foci of mouse urinary bladder carcinomas induced by N-butyl-N-(4- hydroxybutyl)nitrosamine

In a variety of human malignancies, alteration of the p53 tumour suppressorgene is known as a significant indicator of late progression eventsincluding invasion and metastasis, with a possible close relationship togenetic instability. Mutational analysis of the p53 and H-ras genes wasperformed for 10 pairs of N-butyl-N-(4- hydroxybutyl)nitrosamine-inducedinvasive mouse urinary bladder carcinomas and metastatic foci. p53Mutations were found in nine of 10 (90%) primary carcinomas and seven of 10(70%) metastatic foci. A total of eight p53 mutations in primary carcinomaswere common in metastatic foci in six pairs. Additional p53 or H-rasmutations which were not identified in the primary carcinomas were found inthree metastatic foci. Evaluation of the allelic distribution of the p53mutations using RT-PCR, PCR and subcloning, further indicated possibleintra-tumour genomic heterogeneity or excess copy numbers of the p53 genedue to genetic instability. Overall, p53 alterations were frequent in mouseurinary bladder carcinomas demonstrating progression. The results suggestthat genetic instability might underlie generation of additional geneticalterations in this animal model.