Oral communication, iL43

Official XXIst International Pigment Cell Conference website - 21-24 Sept 2011, Bordeaux - France | updated: September 04 2011

The xeroderma pigmentosum syndrome: clinical, genetic and gene therapy issues

Xeroderma pigmentosum (XP) is a rare, genetic DNA repair-deficient disease associated with profound sensitivity to sunlight and early onset of skin cancers. Various skin manifestations, ocular abnormalities and sometimes neurologic symptoms are found in severe forms of the disease. One of the seven genes (XPA to XPG) is mutated in classical XP, which is deficient in nucleotide excision repair (NER), while the POLH gene is mutated in the variant form of XP. The most common form in the world is the XP-C group. The XPC protein is involved in the early recognition of bulky DNA adducts on the non-transcribed genome. Germinal mutations on the XPC gene, with founder effect, have been found in North Africa and in the black population of Mayotte, a French island in the Indian Ocean, where we found the highest world prevalence of XP-C patients. The age of these mutations have been calculated to be, at least, as old as 1200 or 800 years, respectively. Comparison between white-skinned Caucasian and black-skinned XP-C patients reveals major differences in terms of prevalence of skin cancers and ocular manifestations, confirming the major protection effect of melanin toward skin cancers, even in DNA repair-deficient patients. No treatment does exist for XP, except a full protection against UV-exposure. Genetic correction of XP-C skin cells (fibroblasts and keratinocytes) has been successfully obtained by using retroviruses expressing the wild type XPC gene or by using homologous recombination with plasmid DNA coding part of wild type XPC sequences. These complemented cells could be used in the future to produce small patches of corrected XP-C skin in vitro with the project of gene therapy. The NER pathway is able to remove a wide spectrum of bulky DNA lesions, including most damage induced by antitumoral drugs. Sensitivity or resistance of numerous human cancers to various chemotherapies, such as cisplatin or doxorubicin, is partially linked to the efficacy of NER. Genetic polymorphisms or mutations on the NER genes could be associated to therapy response and patient survival. It is important for clinicians to remember that non-tumoral cells of XP patients are very sensitive to antitumoral drugs and that cancer therapy should be adjusted for these patients when they are treated against tumors.

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