Sunburn and p53 in the onset of skin cancer

SQUAMOUS cell carcinoma of the skin (SCC) can progress by stages: sun-damaged epidermis, with individual disordered keratin-ocytes; actinic keratosis (AK), spontaneously regressing keratin-ized patches having aberrant cell differentiation and proliferation; carcinoma in situ; SCC and metastasis^1-3. To understand how sunlight acts as a carcinogen, we determined the stage at which sunlight mutates the p53 tumour-suppressor gene and identified a function for p53 in skin. The p53 mutations induced by ultraviolet radiation and found in >90% of human SCCs^4,5 were present in AKs. Inactivating p53 in mouse skin reduced the appearance of sunburn cells⁶, apoptotic keratinocytes generated by overexposure to ultraviolet. Skin thus appears to possess a p53-dependent 'guardian-of-the- tissue' response to DNA damage which aborts precancerous cells. If this response is reduced in a single cell by a prior p53 mutation, sunburn can select for clonal expansion of the p53-mutated cell into the AK. Sunlight can act twice: as tumour initiator and tumour promoter.