Carcinogenesis Advance Access originally published online on October 25, 2006
Carcinogenesis 2007 28(3):724-731; doi:10.1093/carcin/bgl191
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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
Laboratoire Génomes et Cancers, FRE2939 CNRS, Institut Gustave-Roussy, PRII, 39 Rue Camille Desmoulins 94805 Villejuif, France
1 Institut Gustave-Roussy, 39 Rue Camille Desmoulins 94805 Villejuif, France
2 Departement de nephrologie, Kremlin Bicêtre Hospital 94275 Le Kremlin Bicêtre, France
3 Present address: Departement de Dermatologie, Hopital Cochin-Saint Vincent de Paul 75006 Paris, France
*To whom correspondence and requests for reprints should be addressed at: Laboratoire Génomes et Cancers, FRE2939 CNRS, Institut Gustave-Roussy, PRII, 39 Rue Camille Desmoulins, 94805 Villejuif, France; Tel: 33 1 42 11 63 25; Fax: 33 1 42 11 50 08; E-mail: daya{at}igr.fr
Immunosuppressed renal transplant recipients (RTRs) are predisposed to non-melanoma skin cancers (NMSCs), predominantly squamous cell carcinomas (SCCs). 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, 1 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 and 79% SCCs). Thus, immunosuppression has increased the risk of infections by HPVs, predominantly epidermodysplasia verruciformis, speculated to play a role in 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.
Abbreviations: AK, actinic keratosis; BCCs, basal cell carcinomas; CsA, cyclosporin A; HPV, human papillomas virus; NMSCs, non-melanoma skin cancers; RTRs, renal transplant recipients; SCCs, squamous cell carcinomas
Received July 31, 2006; revised September 21, 2006; accepted October 3, 2006.