Association between DNA repair-deficiency and high level of p53 mutations in melanoma of xeroderma pigmentosum

Xeroderma pigmentosum (XP) is an inheritable disease characterized by sun-s ensitivity and a high frequency of skin cancers including melanoma, We have analyzed two different groups of XP: the XP complementation group C (XP-C) , deficient in global nucleotide excision repair but proficient in transcri ption-coupled repair and associated with a very early onset of skin cancers ; and the XP variant (XPV), deficient in the bypass of DNA photoproducts. T o get new insights into the biology of melanoma in XP patients, we studied 20 melanomas from four XP-C and two XPV patients in terms of pathology, imm unohistochemistry of p53, mutations in exons 4-9 of the p53 gene, and polym orphisms of the p53 gene at codon 72. All statistical tests were two-sided. The majority of the XP melanomas were of the lentigo maligna melanoma (LMM ) type, as found in the elderly, p53 point mutations were found in 60% of X P-C melanomas and in only 10% of XPV melanomas, this latter frequency being similar to what has been reported in the general population, Mutations sho w the specific UV-signature because the majority were CC to TT tandem and C to T transitions located at the bipyrimidine sites known to be hotspots of UV-induced DNA lesions. All DNA lesions giving rise to mutations in XP-C m elanomas were located on the nontranscribed strand of the p53 gene, demonst rating that these patients' cells were able to carry out preferential repai r in vivo. The LMMs found in XP-C are associated with an accumulation of un repaired DNA lesions and may represent a good model for the LMM induction i n the elderly.