Journal Article

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, Nicolien Kram, Anja Westerman, Sander Banus, Henk J. van Kranen and Frank R. de Gruijl

in Carcinogenesis

Volume 26, issue 12, pages 2123-2130
Published in print December 2005 | ISSN: 0143-3334
Published online July 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi198
Relationship between UV-induced mutant p53 patches and skin tumours, analysed by mutation spectra and by induction kinetics in various DNA-repair-deficient mice

More Like This

Show all results sharing this subject:

  • Clinical Cytogenetics and Molecular Genetics

GO

Show Summary Details

Preview

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/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 (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.

Keywords: AK, actinic keratoses; BCC, basal cell carcinoma; CPD, cyclobutane pyrimidine dimers; PBS, phosphate-buffered saline; SCC, squamous cell carcinoma

Journal Article.  7119 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.