Analysis of Sun-Damaged Skin and Epidermal p53 Clones

University dissertation from Uppsala : Acta Universitatis Upsaliensis

Abstract: Sun-damaged skin is a relevant target tissue for studying the development of skin cancer. The aim of the present study was to investigate the epidermal response to ultraviolet radiation (UVR) in human skin in vivo and in vitro and to explore the mutagenic effect of UVA. The prevalence and the genetic background of epidermal p53 clones were furthermore analysed.Large inter- and intraindividual differences were observed in the epidermal response to UVR. Repair of UV-induced DNA damage appeared more efficient in chronically sun-exposed skin than in non-sun-exposed skin. Irradiation with UVA1 induced p53 mutations in keratinocytes. The pattern of mutations was indicative of oxidative damage, consistent with UVA acting as a mutagen.The prevalence of p53 clones in skin adjacent to basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and benign melanocytic nevus in patients of different age groups was analysed. An age-dependent increase in number and size of p53 clones was observed. Epidermal p53 clones were significantly larger and more frequent in skin adjancent to SCC than adjacent to BCC or melanocytic nevus. Mutation analysis of the entire coding region of the p53 gene showed that 57% of p53 clones in normal skin surrounding BCC and SCC have a mutated p53 gene. In conclusion, this study has increased our knowledge of the effects of UVR in chronically sun-exposed skin. The mutation spectra observed in epidermal p53 clones resembled that of non-melanoma skin cancer. The increased prevalence of epidermal p53 clones adjacent to SCC indicates that epidermal p53 clones may represent a step prior to actinic keratosis in the development of SCC.