P53 Gene Mutations in Human Skin Cancers
Laboratory of Genetic Instability & Cancer, IGR-CNRS, -Villejuif, France
Skin cancers are the most frequent human malignancies and are in constant increased incidence for the last 20 years. The life-style of increased sun exposure is partly responsible for this high frequency. Non-melanoma skin cancers (Basal cell carcinomas and squamous cell carcinomas) are relatively easily cured while malignant melanomas are very aggressive tumours that metastasize rapidly. Skin tumours are essentially linked to too much sun exposure, especially in infancy. UVB and UVA radiations produce DNA lesions that if, not properly repaired by the nucleotide excision repair pathway, may lead to targeted mutations. These mutations are due to replication by specialized DNA polymerases of pyrimidine-pyrimidine dimers specific of UV-irradiation. Most of theses mutations are C to T transitions or CC to TT tandem mutations. The fundamental role of DNA repair pathways and specialized translesion polymerases is attested by the existence of very dramatic DNA repair diseases. Classical xeroderma pigmentosum patients and xeroderma pigmentosum variant patients exhibit sun sensitivity and a very high incidence of skin cancers due to a defect in nucleotide excision repair or in the translesion polymerase eta, respectively. The gene p53 is mutated in numerous human cancers. We have used it as a molecular target to characterize the induction of mutations in human skin cancers. About 50 % of all skin cancers in normal individuals exhibit p53 mutations, this frequency rises to 90 % in skin cancers of xeroderma pigmentosum patients. These mutations are characterized by a specific signature, attributed to the UVB part of the solar spectrum. P53 mutations spectra vary in relation to the different histopathological types of skin cancers, as well as to the DNA repair efficiency of the patients. In particular, different mutational hot spots are found amongst the various spectra. We have tried to elucidate them in terms of induced DNA lesion hot spots, as well as speed of local repair of sequence effects. Melanomas from young xeroderma pigmentosum patients resemble the lentigo maligna melanoma found in the elderly. More p53 mutations are found in this type of tumours than in classical melanoma. Again, these mutations are due to the accumulation of unrepaired UV-induced DNA lesions. The molecular analysis of these mutagenic characteristics allows us to better understand the origin of human skin cancers.
Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in plenary session 801 (Predictive markers & validation).