Copyright © 2001 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 68, Issue 4, 884-894, 1 April 2001
doi:10.1086/319500
Melanocortin-1 Receptor Gene Variants Determine the Risk of Nonmelanoma Skin Cancer Independently of Fair Skin and Red Hair
Maarten T. Bastiaensa, Jeannet A. C. ter Huurnea, Christine Kielicha, Nelleke A. Gruisa, Rudi G.J. Westendorpb, Bert Jan Vermeera, Jan Nico Bouwes Bavincka, 
, 
, for the Leiden Skin Cancer Study Team*
a Departments of Dermatology University Medical Centre, Leiden, The Netherlands
b Departments of Clinical Epidemiology, Leiden University Medical Centre, Leiden, The Netherlands
Address for correspondence and reprints: Dr. J. N. Bouwes Bavinck, Department of Dermatology, Leiden University Medical Centre, P.O. Box 9600, 2300 RC Leiden, The Netherlands* Members of the Leiden Skin Cancer Study Team are Nathalie van Amsterdam, Wilma Bergman, Marjo Berkhout, Ingeborg Boxman, René Broer, Jan Anthonie Bruijn, Marianne Crijns, Mariet Feltkamp, Sofie De Hertog, Juliette Hoefnagel, Kees Kennedy, Iris Kuijken, Sjan Lavrijsen, Linda Mulder, Marloes Polderman, Marinus van Praag, Jan ter Schegget, Caesar Sterk, Linda Struijk, and Christianne Wensveen.
Abstract
Melanocortin-1 receptor (MC1R) gene variants are associated with fair skin and red hair and, independently of these, with cutaneous malignant melanoma. The association of MC1R gene variants with nonmelanoma skin cancer is largely unknown. A total of 838 subjects were included in the present study: 453 patients with nonmelanoma skin cancer and 385 subjects with no skin cancer. The coding sequence of the human MC1R gene was tested using single-stranded conformation polymorphism analysis followed by sequencing of unknown variants. Risk of skin cancer dependent on the various MC1R gene variants was estimated using the exposure odds ratio. We investigated whether subjects with MC1R variant alleles were at increased risk of developing nonmelanoma skin cancer and, if so, whether this increased risk was mediated by fair skin and red hair. A total of 27 MC1R gene variants were found. The number of carriers of one, two, or three MC1R gene variants was 379 (45.2%), 208 (24.8%), and 7 (0.9%), respectively. A strong association between MC1R gene variants and fair skin and red hair was established, especially the variants Arg151Cys and Arg160Trp (P<.0001). Carriers of two variant alleles were at increased risk for developing cutaneous squamous cell carcinoma (odds ratio 3.77; 95% confidence interval [CI] 2.11–6.78), nodular basal cell carcinoma (odds ratio 2.26; 95% CI 1.45–3.52), and superficial multifocal basal cell carcinoma (odds ratio 3.43; 95% CI 1.92–6.15), compared with carriers of two wild-type alleles. Carriers of one variant allele had half the risk. The highest relative risks of nonmelanoma skin cancer were found in carriers of the Asp84Glu, His260Pro, and Asp294His variant alleles, and the risk was only slightly lower for carriers of the Val60Leu, Val92Met, Arg142His, Arg151Cys, and Arg160Trp variant alleles. When subjects were stratified by skin type and hair color, analysis showed that these factors did not materially change the relative risks. These findings indicate that MC1R gene variants are important independent risk factors for nonmelanoma skin cancer.
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