THE ROLE OF UV-B LIGHT IN SKIN CARCINOGENESIS THROUGH THE ANALYSIS OFP53 MUTATIONS IN SQUAMOUS-CELL CARCINOMAS OF HAIRLESS MICE

Mutation spectra of the p53 gene from human skin carcinomas have been connected to solar UV radiation, For comparison we have characterized the mutation spectrum of the p53 gene in a very large sample of squamo us cell carcinomas from hairless mice induced with UV of wavelength 28 0-320 nm (UV-B), which have substantiated the mutagenic effects of UV- B radiation in vivo. Tumors from hairless mice, random bred SKH:HR1 as well as inbred SKH:HRA strains, which are analyzed for mutations in t he conserved domains of the p53 protein present a very specific mutati on spectrum, The observed mutation frequency after chronic UV-B radiat ion in the p53 gene ranged from 54% (SKH-HRA) to 73% (SKH-HR1) among t he 160 tumors analyzed, Over 95% of the mutations were found at dipyri midine sites located in the non-transcribed strand, the majority were C-->T transitions and 5% were CC-->TT tandem double mutations, Four di stinct UV-B mutation hot spots have been identified for the first time : two major ones at codons 267 (33%) and 272 (19%) and two minor ones at codons 146 (10%) and 173 (4%), The codon 267 hot spot consists of a CPG preceded by a pyrimidine, which confirms in vivo an important rol e for this UV-B mutable site in UV-B-induced skin tumors that is not f ound in other types of mouse tumors, Comparison with mutation spectra from human skin carcinomas fully validates the merits of the hairless mouse model for studying the molecular mechanisms of skin carcinogenes is, For example, the murine hot spot at codon 272 does have a full equ ivalent in human skin carcinomas. In contrast, the human equivalent of the murine codon 267 lacks the dipyrimidine site and therefore fails to be a pronounced hot spot in human skin carcinomas; however, this si te is one of the major hot spots in human internal cancers (evidently not induced by UV radiation but probably by deamination of the 5 methy l cytosine).