Early events in UV carcinogenesis--DNA damage, target cells and mutant p53 foci.
Skin carcinomas are the most common cancers in fair-skinned populations of North West European descent. The risk is closely related to sun (UV) exposure and susceptibility to sunburn. Induction of squamous cell carcinomas (SCCs) in the skin of hairless mice by daily UVB exposure appears to emulate the genesis of these tumors in humans quite well. The carcinomas, and the UVB signature mutations that they carry in their p53 genes, can be linked most specifically to the induction of cyclobutane pyrimidine dimers (CPDs). The wavelength dependence of the induction of carcinomas parallels that of CPD induction over the UVB and UVA2 spectral regions. Microscopic clusters of cells overexpressing p53 with UVB signature mutations ("p53 patches") can be detected in the interfollicular epidermis long before the skin tumors arise. DNA repair--more precisely nucleotide excision repair--is a crucial line of defense against UV-induced p53 patches and skin carcinomas. Although chemoprevention of UV carcinogenesis, e.g. with difluoromethylornithine, may be successful by inhibiting the outgrowth of tumors, it may be better to counter the initial steps in tumor development. As the p53 patches appear to be potential precursors of SCCs, regression of p53 patches in unexposed skin should lower subsequent development of SCCs. However, "holoclonal" p53 patches might persist. Ablation of the interfollicular epidermis would be expected to abrogate development of SCC, and negation of this expectation [Faurschou A. et al., Exp. Dermatol. 2007;16:485-489] would indicate that SCCs stem from deep-seated cells in the hair follicles. Careful examination of archival material showed that although most small p53 patches arise interfollicularly, some may actually arise high up in a follicle, in the infundibulum.
de Gruijl
Frank R
FR
Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands. f.r.de_gruijl@lumc.nl
Rebel
Heggert
H
D000818:Animals; D004249:DNA Damage; D006801:Humans; D051379:Mice; D009154:Mutation; D009381:Neoplasms, Radiation-Induced; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014466:Ultraviolet Rays
D016159:Tumor Suppressor Protein p53