Assessment of 3 xeroderma pigmentosum group C gene polymorphisms and risk of cutaneous melanoma: a case–control study

• Published in: Carcinogenesis (New York) Vol. 26; no. 6; pp. 1085 - 1090
• Main Authors: Blankenburg, Sandra, König, Inke R., Moessner, Rotraut, Laspe, Petra, Thoms, Kai-Martin, Krueger, Ullrich, Khan, Sikandar G., Westphal, Goetz, Berking, Carola, Volkenandt, Matthias, Reich, Kristian, Neumann, Christine, Ziegler, Andreas, Kraemer, Kenneth H., Emmert, Steffen
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.06.2005; Oxford Publishing Limited (England)
• Subjects: Adult; Alleles; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Case-Control Studies; CDK; cyclin D kinase; Exons; Female; Genetic Predisposition to Disease; Genotype; Germany; Humans; Introns; Medical sciences; Melanoma - genetics; Middle Aged; NER; nucleotide excision repair; Polymorphism, Genetic; Risk; single nucleotide polymorphism; Skin Neoplasms - genetics; SNP; Tumors; xeroderma pigmentosum; Xeroderma Pigmentosum - genetics; XP variant; XPV; Germany; Human; Photosensitivity; Skin disease; Pigmentation disorder; Genetic variability; Xeroderma pigmentosum; Genotype; Malignant tumor; Case control study; Genetic disease; Case study; Photodermatosis; Risk factor; Malignant melanoma
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgi055

Individuals with the rare DNA repair deficiency syndrome xeroderma pigmentosum (XP) are sensitive to the sun and exhibit a 1000-fold increased risk for developing skin cancers, including cutaneous melanoma. Inherited polymorphisms of XP genes may contribute to subtle variations in DNA repair capacity and genetic susceptibility to melanoma. We investigated the role of three polymorphic alleles of the DNA repair gene XPC in a hospital-based case–control study of 294 Caucasian patients from Germany who had cutaneous melanoma and 375 healthy cancer-free sex-matched Caucasian control subjects from the same area. We confirmed that the XPC intron 9 PAT+, intron 11 −6A, and the exon 15 2920C polymorphisms are in a linkage disequilibrium. Only 1.6% of the 669 donors genotyped were discordant for these three polymorphisms. The allele frequencies (cases: controls) were for intron 9 PAT+ 41.7%:36.9%, for intron 11 −6A 41.8%:37.0% and for exon 15 2920C 41.3%:37.3%. Using multivariate logistic regression analyses to control for age, skin type and number of nevi, the three polymorphisms were significantly associated with increased risks of melanoma: OR 1.87 (95% CI: 1.10–3.19; P = 0.022), OR 1.83 (95% CI: 1.07–3.11; P = 0.026), and OR 1.82 (95% CI: 1.07–3.08; P = 0.026), respectively. Exploratory multivariate analyses of distinct subgroups revealed that these polymorphisms were associated with increased risks for the development of multiple primary melanomas (n = 28). The results of our case–control study support the hypothesis that the intron 9 PAT+, intron 11 −6A and exon 15 2920C haplotype may contribute to the risk of developing cutaneous melanoma by increasing the rate of an alternatively spliced XPC mRNA isoform that skips exon 12 and leads to reduced DNA repair. Our results should be validated in independent samples in order to guard against false positive findings.