p53 Mutation in Squamous Cell Carcinomas from Psoriasis Patients Treated with Psoralen + UVA (PUVA)

Individuals suffering from psoriasis are treated with a combination of psoralen and UVA radiation, commonly referred to as "PUVA" therapy. Epidemiologic studies have shown that PUVA therapy is a risk factor for skin cancer in psoriasis patients. Although PUVA treatment induces skin cancer in laboratory animals, it is unknown whether the increased incidence of skin cancer reported in PUVA-treated psoriasis patients is due to the carcinogenic effects of PUVA or due to other factors such as UVB. Because CV and PUVA induce different types of DNA damage resulting in unique types of p53 mutation, we investigated whether skin cancers from PUVA-treated psoriasis patients have PUVA-type or UV-type p53 mutations. Analysis of 17 squamous cell carcinomas (SCCs) from Austrian PUVA-treated patients revealed a total of 25 p53 mutations in 11 SCCs. A majority of p53 mutations occurred at 5'TpG sites. Although previous studies have shown that 5'TpA sites are the primary targets for PUVA mutagenesis, substitutions at 5'TpG sites are also quite common. Interestingly, a sizable portion of p53 mutations detected were C→T or CC→TT transitions, characteristic of UV-induced mutations. Because some psoriasis patients had substantial exposure to UVB before PUVA therapy and because the light sources used in PUVA therapy contained small but significant wave-lengths in the UVB region, it is possible that the C→T and CC→TT transitions detected in SCCs from PUVA-treated patients were induced by UVB. Nonetheless, our results indicate that both PUVA and UVB may play a role in the development of skin cancer in Austrian psoriasis patients who undergo PUVA therapy

Platelet-activating factor is crucial in psoralen and ultraviolet A-induced immune suppression, inflammation, and apoptosis.

Psoralen plus UVA (PUVA) is used as a very effective treatment modality for various diseases, including psoriasis and cutaneous T-cell lymphoma. PUVA-induced immune suppression and/or apoptosis are thought to be responsible for the therapeutic action. However, the molecular mechanisms by which PUVA acts are not well understood. We have previously identified platelet-activating factor (PAF), a potent phospholipid mediator, as a crucial substance triggering ultraviolet B radiation-induced immune suppression. In this study, we used PAF receptor knockout mice, a selective PAF receptor antagonist, a COX-2 inhibitor (presumably blocking downstream effects of PAF), and PAF-like molecules to test the role of PAF receptor binding in PUVA treatment. We found that activation of the PAF pathway is crucial for PUVA-induced immune suppression (as measured by suppression of delayed type hypersensitivity to Candida albicans) and that it plays a role in skin inflammation and apoptosis. Downstream of PAF, interleukin-10 was involved in PUVA-induced immune suppression but not inflammation. Better understanding of PUVA\u27s mechanisms may offer the opportunity to dissect the therapeutic from the detrimental (ie, carcinogenic) effects and/or to develop new drugs (eg, using the PAF pathway) that act like PUVA but have fewer side effects

Oncogenic potential of BRAF versus RAS

Mutations in the ERK pathway occur in approximately one-third of all human cancers and most often involve production of mutant RAS or BRAF. Several studies, including our own, have shown that mutations in the BRAF and RAS genes are generally mutually exclusive. This study was performed to determine the relative oncogenic potential of the BRAF and RAS oncogenes. BRAF V600E -, H-RAS G12V -, and N-RAS Q61R -transfected mouse embryonic fibroblasts (MEFs) that lack p53 (p53 −/−) or contain mutations at codon 172 (p53 R172H and p53 R172P) were able to induce morphologically transformed foci in p53 −/− and p53 R172H MEFs but not in p53 R172P MEFs. Interestingly, BRAF V600E was less potent than mutant H-RAS G12V or N-RAS Q61R was in cooperating with mutant p53 as the numbers and sizes of foci induced by BRAF V600E were significantly lower and smaller. In vitro growth characteristics and anchorage-independent growth of transfected MEFs corroborated the transformed phenotype, and in vivo tumorigenesis confirmed the results. These results indicate that mutant BRAF V600E is weakly oncogenic compared with mutant RAS and that they both cooperate with p53 −/− and p53 R172H but not with p53 R172P in oncogenic transformation

p53 and the pathogenesis of skin cancer

The p53 tumor suppressor gene and gene product are among the most diverse and complex molecules involved in cellular functions. Genetic alterations within the p53 gene have been shown to have a direct correlation with cancer development and have been shown to occur in nearly 50% of all cancers. p53 mutations are particularly common in skin cancers and UV irradiation has been shown to be a primary cause of specific ‘signature’ mutations that can result in oncogenic transformation. There are certain ‘hot-spots’ in the p53 gene where mutations are commonly found that result in a mutated dipyrimidine site. This review discusses the role of p53 from normal function and its dysfunction in pre-cancerous lesions and non-melanoma skin cancers. Additionally, special situations are explored, such as Li-Fraumeni syndrome in which there is an inherited p53 mutation, and the consequences of immune suppression on p53 mutations and the resulting increase in non-melanoma skin cancer in these patients