Relationship between UV-induced mutant p53 patches and skin tumours, analysed by mutation spectra and by induction kinetics in various DNA-repair-deficient mice.
Clusters of p53 immunopositive epidermal keratinocytes (so-called p53 patches, clones or foci) are found in sun or ultraviolet (UV) light-exposed skin. We investigated to what extent these p53 patches are genuine precursors of skin carcinomas in chronically irradiated hairless (SKH1) mice. The mutation spectra of exons 5-8 of the p53 gene of laser-micro-dissected mutant p53 patches and carcinomas were therefore compared. The mutations we found were mainly UV-signature mutations (C-->T and CC-->TT at dipyrimidine sites) located at known hotspots. No significant differences were found between both spectra, indicating that all p53 patches harbour mutations with which they could progress to carcinomas. To examine whether these p53 patches can be used as tumour risk indicators, we made an extensive comparison of the induction kinetics of these patches and carcinomas in genetically modified mice with various defects in nucleotide excision repair (NER), i.e. xeroderma pigmentosum A (Xpa), Xpc and Cockayne syndrome B (Csb) and wild-type mice. In this aforementioned order, the mouse strains developed both p53 patches and carcinomas in the course of daily exposure to 40 J/m(2) UV. Hence, the order in which the NER-deficient mice developed patches was predictive of the order in which they developed tumours. The induction kinetics of the patches in Xpc-deficient mice differed notably from the others: there was a stationary phase (days 13-41) where the numbers were limited to 5-10 patches per mouse before an explosive increase which ran parallel to the other groups. The chance that a p53 patch progresses to carcinoma is relatively small (estimated at 1 out of 8300-40,000/individual when the first tumour appears), but our results are strongly indicative of a causal relationship between p53 patches and carcinomas.
Rebel
Heggert
H
Department of Dermatology, Leiden University Medical Centre, Sylvius Laboratory, Leiden, The Netherlands.
Kram
Nicolien
N
Westerman
Anja
A
Banus
Sander
S
van Kranen
Henk J
HJ
de Gruijl
Frank R
FR
D000818:Animals; D003057:Cockayne Syndrome; D003433:Crosses, Genetic; D004265:DNA Helicases / Q000235:genetics / Q000502:physiology; D004260:DNA Repair / Q000502:physiology*; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D004307:Dose-Response Relationship, Radiation; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D006579:Heterozygote; D007700:Kinetics; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics*; D009381:Neoplasms, Radiation-Induced / Q000209:etiology* / Q000378:metabolism; D000075223:Poly-ADP-Ribose Binding Proteins; D012307:Risk Factors; D012867:Skin / Q000378:metabolism* / Q000528:radiation effects*; D012878:Skin Neoplasms / Q000209:etiology* / Q000378:metabolism; D013472:Sunlight; D014466:Ultraviolet Rays; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics / Q000502:physiology
D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; C501002:Xpc protein, mouse; D004265:DNA Helicases; C513075:Ercc6 protein, mouse; D045643:DNA Repair Enzymes