Carcinogenesis, Vol. 20, No. 4, 715-718,
April 1999
© 1999 Oxford University Press
LOH and mutational analysis of p53 alleles in mouse urinary bladder carcinomas induced by N-butyl-N-(4-hydroxybutyl) nitrosamine
First Department of Pathology, Osaka City University Medical School, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585 and
1 Aburahi Laboratories, Shionogi Research Laboratories, Shionogi Co. Ltd, Gonda, Koka-chou, Koka-gun, Shiga 520-34, Japan
In human urinary bladder carcinogenesis, alterations in the p53 tumor suppressor gene are common events. We have previously reported that they are also frequent in invasive urinary bladder carcinomas induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in NON/Shi mice. To further investigate the significance of the p53 gene status for mouse urinary bladder carcinogenesis, we examined both allele loss and mutational alterations in urinary bladder cancers of (NON/ShixC3H/He/Shi) F1 hybrid mice exposed to the carcinogen for 12 weeks and then maintained for a further 9 weeks without treatment. An intragenic silent polymorphism within exon 7 of the p53 gene between NON/Shi and C3H/He/Shi mice allows assessment of allele loss of the p53 gene and determination of the parental origin of mutated and/or lost alleles. A tissue microdissection method was employed to obtain carcinoma samples without excessive contamination with normal tissue. Allele losses were detected in one of 14 tumors (7.1%) and nine mutations in eight of 14 (57%) tumors were found in exons 5–8 by polymerase chain reaction–single strand conformation polymorphism followed by DNA direct sequencing analysis. All mutations involved one base substitution with an amino acid change, although the types of base substitution were random. In conclusion, the high incidence of p53 alterations suggests a significant role in the genesis of invasive urinary bladder tumors in BBN-treated mice.
Abbreviations: BBN, N-butyl-N-(4-hydroxybutyl)nitrosamine; LOH, loss of heterozygosity; PCR, polymerase chain reaction; SCC, squamous cell carcinoma; SSCP, single strand conformation polymorphism; TCC, transitional cell carcinoma.
2 To whom correspondence should be addressed Email: m3886644{at}misc.med.osaka-cu.ac.jp
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