MUTATIONS IN THE P53 TUMOR-SUPPRESSOR GENE IN RAT ESOPHAGEAL PAPILLOMAS INDUCED BY N-NITROSOMETHYLBENZYLAMINE

Mutations in the p53 tumor suppressor gene have been implicated in the pathogenesis of a wide variety of human neoplasms, The location and t ype of p53 gene mutation can reflect exposure of humans to certain typ es of carcinogenic agents, Much less is known about the role of p53 mu tational inactivation in rodent tumors, Using both 'Hot' (radioactive) and 'Cold' (non-radioactive) single strand conformation polymorphism (SSCP) analyses, the present study analyzed exons 5-8 and the exon-int ron junction of the p53 gene from rat esophageal papillomas induced by N-nitsosomethylbenzylamine (NMBA) for mutations, Nine of 30 (30%) eso phageal papillomas contained SSCP mobility shifts, principally within exons 5 and 7, These positive SSCP findings were further validated by direct DNA sequencing analysis, Eight of the nine mutations were G:C-- >A:T transitions in codons 131, 149, 153, 242 (2), 243, 248, and the 5 end of intron 7, None of these G:C-->A:T mutations occurred at the CP G sites, The other mutation was a frameshift mutation in codon 176, Th e G:C-->A:T transitions observed in this study are consistent with the documented formation of O-6-methylguanine adducts in DNA by N-nitroso compounds, These results suggest that point mutations of the p53 gene are involved in the development of approximately one-third of NMBA-in duced rat esophageal papillomas, 'Hot' and 'Cold' SSCP methods were eq ually sensitive for the identification of mutations in the rat p53 gen e.