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Mutations in the p53 tumor suppressor gene in rat esophageal papillomas induced by N-nitrosomethylbenzylamine
1Department of Pathology and Laboratory of Cancer Chemoprevention and Etiology. The Ohio State University Columbus, OH 43210
2School of Public Health and Laboratory of Cancer Chemoprevention and Etiology, The Ohio State University Columbus, OH 43210
3Clinical Research and Review Staff, Office of Special Nutritionals, United States Food and Drug Administration Laurel, MD 20708, USA
4To whom reprint requests should be addressed
Mutations in thep53 tumor suppressor gene have been implicated in the pathogenesis of a wide variety of human neoplasms. The location and type of p53 gene mutation can reflect exposure of humans to certain types of carcinogenic agents. Much less is known about the role of p53 mutational 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-intron junction of the p53 gene from rat esophageal papillomas induced by N-nitrosomethylamine (NMBA) for mutations. Nine of 30 (30%) esophageal 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, 53,242(2), 243, 248, and the 5 end of intron 7. None of these G: C
A: Tmutations occured at the CpG sites. The other mutation was a frameshift mutation in codon 176. The G: CA: T transitions observed in this study are consistent with the documented formation of O6-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-induced rat esophageal papillomas. ‘Hot’ and ‘Cold’ SSCP methods were equally sensitive for the identification of mutations in the rat p53 gene.
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