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Carcinogenesis Advance Access published online on October 25, 2006
Carcinogenesis, doi:10.1093/carcin/bgl191
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received July 31, 2006
Revised September 21, 2006
Accepted October 3, 2006

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Analysis of skin cancer risk factors in immunosuppressed renal transplant patients shows high levels of UV specific tandem CC to TT mutations of the p53 gene

Sophie Queille 1, Lionel Luron 1, Alain Spatz 2, Marie Françoise Avril 3, Vincent Ribrag 2, Pierre Duvillard 2, Christian Hiesse 4, Alain Sarasin 1, Jean Pierre Armand 2, and Leela Daya-Grosjean 1 *

1 Laboratoire Génomes et Cancers, FRE2939 CNRS, Institut Gustave-Roussy, PRII, 39 Rue Camille Desmoulins, 94805 Villejuif, France
2 Institut Gustave-Roussy, 39 Rue Camille Desmoulins, 94805 Villejuif, France
3 Institut Gustave-Roussy, 39 Rue Camille Desmoulins, 94805 Villejuif, France; Present address: Departement de Dermatologie, Hopital Cochin-Saint Vincent de Paul, 75006 Paris, France
4 Departement de nephrologie, Kremlin Bicêtre Hospital, 94275 Le Kremlin Bicêtre, France

* To whom correspondence should be addressed.
Leela Daya-Grosjean, E-mail: daya{at}igr.fr


  Abstract

Immunosuppressed renal transplant recipients (RTR) are predisposed to non-melanoma skin cancers (NMSC), predominantly squamous cell carcinomas (SCC). We have analyzed skin lesions from RTRs with aggressive tumors for p53 gene modifications, the presence of Human Papillomas Virus (HPV) DNA in relation to the p53 codon-72 genotype and polymorphisms of the XPD repair gene. We detected 24 p53 mutations in 15/25 (60%) NMSCs, one deletion and 23 base substitutions, the majority (78%) being UV specific C to T transitions at bipyrimidine sites. Importantly, 35% (6/17) are tandem mutations, including 4 UV signature CC to TT transitions possibly linked to modulated DNA repair caused by the immunosuppressive drug cyclosporin A (CsA). We found 8 p53 mutations in 7/17 (41%) precancerous actinic keratosis (AK), suggesting that p53 mutations are early events in RTR skin carcinogenesis. Immunohistochemical analysis shows a good correlation between p53 accumulation and mutations. HPV DNA was detected in 78% of skin lesions (60% Basal Cell Carcinomas, 82%AK, 79% SCCs). Thus, immunosuppression has increased the risk of infections by HPVs, predominantly epidermodysplasia verruciformis (EV), speculated to play a role skin cancer development. No association is found between HPV status and p53 mutation. Moreover, p53 codon 72 or frequencies of three XPD genotypes of RTRs are comparable with control populations. The p53 mutation spectrum, presenting a high level of CC to TT mutations, shows that the UV component of sunlight is the major risk factor and modulated DNA repair by immunosuppressive drug treatment may be significant in the skin carcinogenesis of RTRs.

Keywords: UV skin cancer; immunosuppressed renal transplant recipient; p53 gene; HPV; p53/XPD gene polymorphisms.
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