The UV component of sunlight is the major carcinogen involved in the etiology of skin cancers. We have studied the rare, hereditary syndrome xeroderma pigmentosum (XP), which is characterized by a very high incidence of cutaneous tumors on exposed skin at an early age, probably due to a deficiency in excision repair of UV-induced lesions. It is interesting to determine the UV mutation spectrum in XP skin tumors in order to correlate the absence of repair of specific DNA lesions and the initiation of skin tumors. The p53 gene is frequently mutated in human cancers and represents a good target for studying mutation spectra since there are >100 potential sites for phenotypic mutations. Using reverse transcription-PCR and single-strand conformation polymorphism to analyze >40 XP skin tumors (mainly basal and squamous cell carcinomas), we have found that 40% (17 out of 43) contained at least one point mutation on the p53 gene. AU the mutations were located at dipyrimidine sites, essentially at CC sequences, which are hot spots for UV-induced DNA lesions.Sixty-one percent of these mutations were tandem CC -k TT mutations considered to be unique to UV-induced lesions; these mutations are not observed in internal human tumors. AU the mutations, except two, must be due to translesion synthesis of unrepaired dipyrimidine lesions left on the nontranscribed strand. These results show the existence of preferential repair of UV lesions [either pyrimidine dimers or pyrimidinepyrimidone (6-4) photoproducts] on the transcribed strand in human tissues.One of the major consequences of UV radiation, a potent DNA-damaging agent, is the induction of skin cancers. In fact, the incidence of cutaneous tumors induced by repeated exposure to sunlight is constantly increasing, making them the most common type of human cancer. The extremely high frequency of malignancies found in exposed skin of individuals with the rare genetic disorder xeroderma pigmentosum (XP) suggests that defective repair of UV-induced DNA damage plays a major role in skin carcinogenesis (1). It has been well characterized that the somatic cells from XP patients are hypersensitive to killing and mutation induction by UV radiation due to a defect in excision repair of UVinduced pyrimidine dimers and/or (6-4) photoproducts (2). Therefore, it is clear that the efficient and accurate removal of DNA lesions by cellular repair processes is critical in order to avoid lethality, mutation, and cellular transformation, which are all important events leading to tumor formation.Carcinogenesis is a complex multistage process, and epidemiological and molecular studies have shown that the induction of cancer may require the accumulation of several independent mutations. In animal skin carcinogenesis, the activation of oncogenes has been well established in the The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. complex...

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