Melanocortin-1 receptor gene variants determine the risk of nonmelanoma skin cancer independently of fair skin and red hair

Maarten T. Bastiaens, Jeannet A.C. Ter Huurne, Christine Kielich, Nelleke A. Gruis, Rudi G.J. Westendorp, Bert Jan Vermeer, Jan Nico Bouwes Bavinck*, 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 LavrijsenLinda Mulder, Marloes Polderman, Marinus Van Praag, Jan Ter Schegget, Caesar Sterk, Linda Struijk, Christianne Wensveen

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

218 Citations (Scopus)


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 Va160Leu, Va192Met, 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.

Original languageEnglish
Pages (from-to)884-894
Number of pages11
JournalAmerican Journal of Human Genetics
Issue number4
Publication statusPublished - Apr 2001
Externally publishedYes


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