Ultraviolet-light induced p53 mutational spectrum in yeast is indistinguishable from p53 mutations in human skin cancer

Ultraviolet (UV) light has been associated with the development of humannon-melanoma skin cancers (NMSC). Such cancers often exhibit mutations inthe p53 tumour suppressor gene. In order to determine the UV-induced p53mutation spectrum, a yeast expression vector that harbours a humanwild-type p53 cDNA was UV-irradiated in vitro and transfected into a yeaststrain that contained the ADE2 gene regulated by a p53-responsive promoter.Forty-five mutant clones contained 51 mutations. Seven mutations weretandem base pair substitutions, four of which being CC-->TT, hallmarkmutations of UV mutagenesis. Eighty percent (41/51) of the mutations weresingle or non-tandem base pair substitutions, the majority of which (27/41)were C-->T transitions. Ninety-five percent of such mutations occurredat dipyrimidine sites. Through a rigorous statistical test, the UV-inducedp53 mutation spectrum appears to differ significantly (P < 0.008) fromthe one induced by the antineoplastic drugchloroethyl-cyclohexyl-nitrosourea, and to be indistinguishable from theone observed in NMSC (P = 0.4). These results demonstrate that the assayallows the determination of carcinogen-specific p53 mutation fingerprintsand represents a new tool for molecular epidemiology.