The role of UV-B light in skin carcinogenesis through the analysis of p53 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 squamous cell carcinomas from hairless mice induced with UV of wavelength 280-320 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 the conserved domains of the p53 protein present a very specific mutation spectrum. The observed mutation frequency after chronic UV-B radiation in the p53 gene ranged from 54% (SKH-HRA) to 73% (SKH-HR1) among the 160 tumors analyzed. Over 95% of the mutations were found at dipyrimidine sites located in the non-transcribed strand, the majority were C-->T transitions and 5% were CC-->TT tandem double mutations. Four distinct 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 role for this UV-B mutable site in UV-B-induced skin tumors that is not found 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 carcinogenesis. For example, the murine hot spot at codon 272 does have a full equivalent 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 site is one of the major hot spots in human internal cancers (evidently not induced by UV radiation but probably by deamination of the 5 methyl cytosine).
Dumaz
N
N
Laboratory of Molecular Genetics, Institut de Recherches sur le Cancer, Villejuif, France.
van Kranen
H J
HJ
de Vries
A
A
Berg
R J
RJ
Wester
P W
PW
van Kreijl
C F
CF
Sarasin
A
A
Daya-Grosjean
L
L
de Gruijl
F R
FR
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D016158:Genes, p53; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D016296:Mutagenesis / Q000528:radiation effects; D009381:Neoplasms, Radiation-Induced / Q000235:genetics*; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D012878:Skin Neoplasms / Q000235:genetics*; D014466:Ultraviolet Rays