XPA-DEFICIENCY IN HAIRLESS MICE CAUSES A SHIFT IN SKIN TUMOR TYPES AND MUTATIONAL TARGET GENES AFTER EXPOSURE TO LOW-DOSES OF UVB

Xeroderma pigmentosum (XP) patients with a defect in the nucleotide ex cision repair gene XPA, develop tumors with a high frequency on sun-ex posed areas of the skin. Here we describe that hairless XPA-deficient mice also develop skin tumors with a short latency time and a 100% pre valence after daily exposure to low doses of U.V.B. Surprisingly and i n contrast to U.V.B.-exposed repair proficient hairless mice who mainl y develop squamous cell carcinomas, the XPA-deficient mice developed p apillomas with a high frequency (31%) at a U.V. dose of 32 J/m(2) dail y, At the highest daily dose of 80 J/m(2) mainly squamous cell carcino mas (56%) and only 10% of papillomas were found in XPA-deficient hairl ess mice, p53 gene mutations were examined in exons 5, 7 and 8 and wer e detected in only 3 out of 37 of these skin tumors, whereas in tumors of control U.V.B.-irradiated wild type littermates this frequency was higher (45%) and more in line with our previous data. Strikingly, a h igh incidence of activating ras gene mutations were observed in U.V.B. -induced papillomas (in 11 out of 14 tumors analysed). In only two out of 14 squamous cell carcinomas we found similar ras gene mutations. T he observed shift from squamous cell carcinomas in wild type hairless mice to papillomas in XPA-deficient hairless mice, and a corresponding shift in mutated cancer genes in these tumors, provide new clues on t he pathogenesis of chemically-versus U.V.B.-induced skin carcinogenesi s.