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Carcinogenesis Advance Access published online on July 28, 2005
Carcinogenesis, doi:10.1093/carcin/bgi198
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received May 25, 2005
Revised July 12, 2005
Accepted July 22, 2005

CANCER BIOLOGY

Relationship between UV-induced mutant p53 patches and skin tumours, analysed by mutation spectra and by induction kinetics in various DNA-repair-deficient mice#

Heggert Rebel 1, Nicolien Kram 2, Anja Westerman 2, Sander Banus 3, Henk J. van Kranen 2, and Frank R. de Gruijl 1*

1 Department of Dermatology, Leiden University Medical Centre, Sylvius Laboratory, P.O. Box 9503, 2300 RA, Leiden, The Netherlands
2 Laboratory of Toxicology, Pathology and Genetics, National Institute of Public of Health Effects Research, PO Box 1, 3720 BA Bilthoven, The Netherlands
3 Laboratory of Vaccine-Preventable Diseases, National Institute of Public of Health Effects Research, PO Box 1, 3720 BA Bilthoven, The Netherlands

* To whom correspondence should be addressed.
Frank R. de Gruijl, E-mail: F.R.de_Gruijl{at}lumc.nl


  Abstract

Clusters of p53 immuno-positive 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 the 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/m2 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 (day 13 - 41) were 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 carcinomas is relatively small (estimated at 1 out of 8,300 to 40,000/individual when the first tumour appears), but our results are strongly indicative of a causal relationship between p53 patches and carcinomas.

# Financed mainly by grant UU97-1531 from the Dutch Cancer Society (KWF).


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