Non-melanoma skin cancer (NMSC) is the most prevalent cancer in the United States with over one million new cases diagnosed each year and incidence rising annually. The most often mutated gene in human cancers, p53 is a critical regulator of cell cycle control, DNA repair, and apoptosis. Loss of functional p53 through mutation can lead to unsuppressed growth and clonal expansion which may eventually give rise to carcinoma. Small case-series studies of keratinocyte carcinomas have reported a mutation prevalence of approximately 50% and an association of the UV signature CC:GG-TT:AA transition with sun exposed areas of the skin. In addition to CC:GG-TT:AA dimer base transitions, the other signature UV radiation induced mutation is a C:G-T:A transition, which generally occurs at a dipyrimidine site. Here, we describe the occurrence of p53 mutation in a large population based study of NMSC in New Hampshire. Study participants had demographic, exposure history, and tumor anatomic site data recorded, and tumors underwent a comprehensive pathology review. 438 tumors were successfully screened for p53 mutation using single strand conformation polymorphism (SSCP) analysis for the DNA binding region of p53 which harbors the majority of mutations and is encoded by exons 5 through 9. Samples with SSCP band shifts were subsequently re-amplified using unlabeled primers and analyzed for mutation by capillary based DNA sequencing. There were 165/438 tumors bearing at least one mutation, giving a p53 mutation prevalence of 37.7%. Of the 165 tumors with any mutation 44, or 26.7% had two or more mutations. Interestingly, 98 of the 223 total mutations or 43.9% were found to be UV signature mutations, with 37.7% of total mutations being the single base C:G-T:A transition, and dimer base transitions accounting for 6.3% of total mutations. Among these 223 total mutations there were four codons satisfying the IARC hot spot criteria, including a novel hot spot at codon 165 which has not previously been reported for NMSC. Two of the four hot spots are classic for p53, occurring at residues involved in zinc binding and direct DNA contact; codons histidine 179 and arginine 248 respectively. The final hot spot occurred at codon 278, directly adjacent to alanine 276 and cysteine 277 both of which directly contact DNA during p53 target transactivation. Thus, in a population based study of p53 mutation in 438 NMSC tumors we characterized the p53 mutation spectra, finding a p53 mutation prevalence of 37.7%, a UV signature mutation prevalence of 43.9%, and a novel hot spot at codon 165.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]