口腔へん平上皮癌におけるｐ５３遺伝子変異の特徴

Abstract

Mutations of the p53 tumor suppressor gene have been found in about 50% of all human cancers. The patterns of tumor-associated p53 mutations are known to be dependent on the primary site and on environmental carcinogens. These characteristics imply molecular linkage between- a particular cancer and specific exogenous or endogenous carcinogens. To clarify the characteristics of the p53 mutational spectrum in oral squamous cell carcinomas (SCCs), we examined p53 mutations in 124 freshly resected specimens of primary oral SCCs by polymerase chain reaction-single-strand conformation polymorphism (PCRSSCP) and direct sequencing.p53 mutations were detected in 53 of 124 (43%) cases. Mutations were equally distributed through exons 5 to 8 and were found in codons 135, 176, 193, and 306 in addition to codons 175, 245, 248, and 273, which are known hotspots. In particular, codon 176 could be a mutational hotspot in oral SCCs. We found that 28% of the mutations were G: C→A: T transitions at the CpG site, which has been implicated in endogenous processes, including methylation and deamination of cytosine. In contrast, only 13% of the mutations were G: C→T: A transversions, which have been implicated in association with exogenous carcinogens. G: C→A: T transitions at non-CpG sites and G: C→T: A transversions occurred preferentially on the nontranscribed coding strand of the p53 gene. Therefore, these mutations may arise from bulky chemical DNA adducts. The present study did not support an association between the nature of p53 mutations and tobacco smoking or alcohol intake.These data suggest that oral carcinogenesis involving p53 mutations is mainly caused by endogenous processes, however, such carcinogenesis may be partially caused by exogenous carcinogens other than tobacco and alcohol.