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

Abstract

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 UV 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 wavelengths 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.

Phosphorylation of Histone H2AX Is a Powerful Tool for Detecting Chemical Photogenotoxicity

“…Notably, damage in a critical gene related to cancer (such as a tumor-suppressor gene) could have catastrophic consequences for the cell. H-ras, INK4a-ARF, and p53 mutations in patients and/or mice treated with 8-MOP plus UVA have been reported (Nataraj et al, 1997;Kreimer-Erlacher et al, 2001, 2003. The mechanism by which the chemicals and UVA generated g-H2AX is worth serious consideration.…”

Increased Prevalence of Human Papillomavirus in Hairs Plucked From Patients With Psoriasis Treated With Psoralen–UV-A

“…Several explanations have been proposed. One theory is that PUVA, which is mutagenic and carcinogenic, may directly initiate skin cancer in patients with psoriasis, perhaps by mutating the tumor suppressor gene p53, [2][3][4] the INK-4a-ARF locus, 5 and/or the protooncogene Ha-ras. 6 A second theory is that PUVA treatment, being immunosuppressive, 7,8 may promote the growth of skin cancers that are induced either by itself or by other suspected or known carcinogenic treatment agents, including UV-B, ionizing radiation, methotrexate, topical tar, and arsenic (for review see Maier et al 9 ).…”

Phototherapie und Karzinogenese

“…Spinozelluläre Karzinome von Psoriasispatienten nach PUVA-Behandlung wiesen zahlreiche Mutationen im Bereich des Tumorsuppressorgens p53 auf. Ein Groß-teil dieser Mutationen fand sich in 5'TpGStellen, die typisch für einen Schaden im Zusammenhang mit Psoralenexposition sind, jedoch fanden sich auch zahlreiche CPD, die auf einen UVB-Schaden hindeuten, sodass bei diesen Tumoren PU-VA zusammen mit UVB aus der Umgebung oder früherer therapeutischer Exposition eine Rolle spielt [29]. Zusätzlich zu Mutationen im Bereich von p53 konnten bei spinozellulären Karzinomen von PUVA-Patienten häufige Ha-ras-Mutationen festgestellt werden, die ebenfalls zur Karzinogenese beitragen können [21].…”