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Carcinogenesis Advance Access published online on February 24, 2005
Carcinogenesis, doi:10.1093/carcin/bgi055
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Published by Oxford University Press 2005
Received October 27, 2004
Revised February 9, 2005
Accepted February 16, 2005

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

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

Sandra Blankenburg 1, Inke R. König 2, Rotraut Moessner 1, Petra Laspe 1, Kai-Martin Thoms 1, Ullrich Krueger 1, Sikandar G. Khan 3, Goetz Westphal 4, Carola Berking 5, Matthias Volkenandt 5, Kristian Reich 1, Christine Neumann 1, Andreas Ziegler 2, Kenneth H. Kraemer 3, and Steffen Emmert 1*

1 Department of Dermatology, Georg-August-University Goettingen, Germany
2 Institute of Medical Biometry and Statistics, University Hospital Schleswig-Holstein - Campus Lübeck, Germany
3 Basic Research Laboratory, Center for Cancer Research, National Cancer Institute/NIH, Bethesda, MD, USA
4 Department of Occupational and Social Medicine, Georg-August-University Goettingen, Germany
5 Department of Dermatology, Ludwig-Maximilians-University Munich, Germany

* To whom correspondence should be addressed.
Steffen Emmert, E-mail: semmert{at}gwdg.de


  Abstract

Individuals with the rare DNA repair deficiency syndrome xeroderma pigmentosum (XP) are sun-sensitive 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 with 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 linkage disequilibrium. Only 1.6% of 669 donors genotyped were discordant for these 3 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, 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.

Keywords: DNA repair; xeroderma pigmentosum; XPC; cutaneous melanoma.
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