CLONES OF NORMAL KERATINOCYTES AND A VARIETY OF SIMULTANEOUSLY PRESENT EPIDERMAL NEOPLASTIC LESIONS CONTAIN A MULTITUDE OF P53 GENE-MUTATIONS IN A XERODERMA-PIGMENTOSUM PATIENT

A patient with xeroderma pigmentosum group C was extensively examined for mutations in the p53 gene in normal skin exposed to varying degree s of sunlight and in excisional biopsies of basal cell cancer, squamou s cell cancer, and squamous cell dysplasia, Seventy-three samples were analyzed by microdissection of small cell clusters, followed by PCR a nd direct DNA sequencing. In skin taken from areas that most likely ha d never been exposed to the sun, no mutations were found. However, in skin exposed to the sun, me observed a multitude of mutations in the p 53 gene. UV light-induced mutations were found in all types of lesions , as well as in clusters of morphologically normal epidermal cells. Tw enty-nine distinct mutations were found in exons 5-8, all missense or nonsense, of which 27 (93%) were UV-specific C --> T or CC --> TT tran sitions at dipyrimidine sites of the nontranscribed strand. Two types of normal skin areas containing p53 mutations were observed: areas tha t stain strongly with p53 antibody (p53 patches) and those that do not stain. Because no silent or intron mutations were found in these cell clusters, the alterations in the p53 gene of morphologically normal c ells are Likely to have resulted in a selective growth advantage. The poor correlation between mutations and morphological phenotypes demons trates that p53 mutations alone do not determine the phenotypes observ ed.