MUTATION HOTSPOTS DUE TO SUNLIGHT IN THE P53 GENE OF NONMELANOMA SKINCANCERS

To identify the sites in the p53 tumor suppressor gene most susceptibl e to carcinogenic mutation by sunlight, the entire coding region of 27 basal cell carcinomas (BCCs) of the skin was sequenced. Fifty-six per cent of tumors contained mutations, and these were UV-like: primarily CC --> TT or C --> T changes at dipyrimidine sites. Such mutations can alter more than half of the 393 amino acids in p53, but two-thirds oc curred at nine sites at which mutations were seen more than once in BC C or in 27 previously studied squamous cell carcinomas of the skin. Se ven of these mutation hotspots were specific to skin cancers. Internal -cancer hotspots not located at dipyrimidine sites were not mutated in skin cancers; moreover, UV photoproducts were absent at these nucleot ides. The existence of hotspots altered the process of inactivating p5 3 in BCC compared to other cancers: allelic loss was rare, but 45% of the point mutations were accompanied by a second point mutation on the other allele. At least one of each pair was located at a hotspot. Sun light, acting at mutation hotspots, appears to cause mutations so freq uently that it is often responsible for two genetic events in BCC deve lopment.