© 2000 by Oxford University Press
Journal of the National Cancer Institute, Vol. 92, No. 22, 1841-1847,
November 15, 2000
© 2000 Oxford University Press
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Association Between INK4a-ARF and p53 Mutations in Skin Carcinomas of Xeroderma Pigmentosum Patients
Affiliations of authors: N. Soufir, L. Dubertret, N. Basset-Seguin (Institut de Recherche sur la Peau, Institut National de la Santé et de la Recherche Medicale [INSERM] U532), P. de La Salmonière (Département de Biostatistique et Informatique Médicale), Hôpital Saint-Louis, Paris, France; L. Daya-Grosjean, A. Sarasin, Molecular Genetics Laboratory, UPR42, Centre National de la Recherche Scientifique, Villejuif, France; J.-P. Moles, Laboratoire de Dermatologie Moléculaire, Institut Universitaire de Recherche Clinique, Montpellier, France.
Correspondence to: Nicole Basset-Seguin, M.D., Ph.D., Institut de Recherche sur la Peau, INSERM U532, Pavillon Bazin, Hôpital Saint-Louis, 1, avenue Claude Vellefaux, 75010 Paris, France (e-mail: nbs{at}chu.st-louis.fr).
Background: The INK4a-ARF locus encodes two tumor suppressor proteins, p16INK4a and p14ARF, that act through the Rb-CDK4 and p53 pathways, respectively. Data from murine models and sporadic human skin carcinomas implicate p16INK4a and p14ARF in the development of skin carcinomas. We examined the frequency of INK4a-ARF, p53, and CDK4 mutations in skin carcinomas from patients with xeroderma pigmentosum (XP), a rare autosomal disease that is associated with a defect in DNA repair and that predisposes patients to skin cancer. Methods: DNA from skin cancers of 28 unrelated XP patients was screened for mutations in p53, INK4a-ARF, and CDK4 coding exons by single-strand conformation polymorphism analysis and automated sequencing. Data were evaluated with the use of the exact unconditional test derived from Fisher's test. All statistical tests were two-sided. Results: Eight of 28 XP-associated tumors had mutations in the INK4a-ARF locus. Three XP-associated tumors had multiple mutations at this locus. In all, 13 mutations in the INK4a-ARF locus were detected in XP-associated tumors, of which seven (54%) were signature UV radiation-induced mutations, i.e., tandem CC : GG
TT : AA transitions. p53 mutations, mostly of the type induced by UV radiation, were present in 12 tumors (43%). Statistically significant positive associations were found between the frequency of mutations in p53 and in p16INK4a (P = .008) and between the frequency of mutations in p53 and in p14ARF (P<.001). No mutations were detected within the CDK4 gene. Conclusions: We have demonstrated for the first time the occurrence of UV radiation-induced mutations in INK4a-ARF in XP-associated skin carcinomas. The simultaneous inactivation of p53 and INK4a-ARF may be linked to the genetic instability caused by XP and could be advantageous for tumor progression.
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