GENETIC ALTERATIONS IN PUVA INDUCED SKIN CANCERS

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A combination of psoralen and ultraviolet-A (320-400 nm) (UVA) radiation, commonly referred to as "PUVA", is being widely used in the treatment of psoriasis. With the wide-spread use of PUVA therapy, considerable attention has been focused on the mutagenic and carcinogenic effects of PUVA. Numerous studies have shown that PUVA treatment induces skin cancer in mice. In addition, several reports indicate that PUVA therapy is a risk factor for skin cancer development in humans. However, the molecular mechanisms that are involved in the pathogenesis of PUVA-induced skin cancers are poorly understood. The long-term goal of this proposal is to identify the genetic alterations that are associated with the origin and development of skin cancer in PUVA treated patients. Since the etiology of human skin cancers arising in psoriasis patients who have undergone PUVA therapy is controversial, it may be possible to use the p53 tumor suppressor gene as a molecular marker and determine whether these skin cancers are induced by UV radiation or by PUVA. Since UV and PUVA induces different types of DNA damage, we hypothesize that mutations induced by these two carcinogenic agents are also different, and thus may leave their unique "signature". Our specific aims are: (1) To identify ras and p53 mutations associated with PUVA-induced mouse skin cancers, (2) To determine whether PUVA-induced ras and p53 mutations are an early or a late event during PUVA carcinogenesis, and (3) To determine whether human skin cancers from psoriasis patients who have undergone PUVA therapy harbor ras and p53 mutations that are similar to those detected in PUVA- induced murine skin cancers. Mutations in ras and p53 genes will be identified by single strand conformation polymorphism analysis and nucleotide sequencing. A thorough clinical evaluation of patient's prior exposure to chemotherapy or radiotherapy, number, duration, and intensity of exposure to PUVA, skin type, etc., will be made to correlate ras and p53 mutation data with clinical data. ras and p53 mutation studies in PUVA, 4,4',6-trimethylangelicin+UVA and angelicin+UVA induced mouse skin tumors should provide important information on the role of monofunctional adducts and DNA cross-links in PUVA carcinogenesis. Information obtained from p53 studies in human skin cancers from PUVA-treated patients may provide clues to the etiology of these skin cancers, which may be useful for the future formulation of intervention protocols.