Frequent mutations of the p53 gene and infrequent H- and K-ras mutations in urinary bladder carcinomas of NON/Shi mice treated with N-butyl-N-(4-hydroxybutyl)nitrosamine.
To elucidate whether common genetic events in human urinary bladder carcinogenesis also occur in rodent models, we investigated the presence of p53, H- and K-ras mutations in 18 urinary bladder carcinomas induced by various concentrations of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in male NON/Shi mice. Histopathologically, all were invasive, 11 being squamous cell carcinomas (SCCs) and the remaining seven being transitional cell carcinomas (TCCs). Using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) analysis followed by DNA sequencing, p53, H- and K-ras mutations were observed in 14 (78%; exons 5-7), two (11%; one each on exons 1 and 2) and one (5.6%; exon 1) animals respectively. The frequencies of mutations in p53 exons 5, 6 and 7 were 7 (39%), 4 (22%), and 9 (50%) respectively, and no mutation was found in exon 8. All mutations involved one base-pair substitution with or without amino acid changes and the types of base-pair substitution were random. No evident association was observed between mutation sites and the histological phenotypes. In conclusion, p53 mutations are frequent in BBN-induced mouse invasive urinary bladder tumors, at similar levels to those observed for human high-grade invasive carcinomas, and this plus their distribution suggests their possible participation in this model of urinary bladder carcinogenesis.
Yamamoto
S
S
Laboratory of Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan.
Masui
T
T
Murai
T
T
Mori
S
S
Oohara
T
T
Makino
S
S
Fukushima
S
S
Tatematsu
M
M
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002085:Butylhydroxybutylnitrosamine / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D002295:Carcinoma, Transitional Cell / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D017931:DNA Primers; D004273:DNA, Neoplasm / Q000737:chemistry; D005091:Exons; D016158:Genes, p53 / Q000187:drug effects*; D011905:Genes, ras / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009361:Neoplasm Invasiveness; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology
D002273:Carcinogens; D017931:DNA Primers; D004273:DNA, Neoplasm; D002085:Butylhydroxybutylnitrosamine