1. ¹Department of Dermatology, University of L'Aquila, L'Aquila, Italy
2. ²Laboratory of Molecular Technology, Advanced Technology Program, SAIC-Frederick Inc., NCI-Frederick, Frederick, Maryland, USA
3. ³Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
4. ⁴Pathology Histotechnology Laboratory, SAIC-Frederick Inc., NCI-Frederick, Frederick, Maryland, USA
5. ⁵Department of Dermatology, Bufalini Hospital, Cesena, Italy
6. ⁶Department of Dermatology, University of Modena and Reggio Emilia, Modena, Italy
7. ⁷Department of Human Pathology and Oncology, University of Florence, Florence, Italy
8. ⁸Department of Dermatology, University of Florence, Florence, Italy
9. ⁹Department of Pathology, University of California at San Francisco, San Francisco, California, USA
10. ¹⁰Department of Pathology, University of Pennsylvania, Philadelphia, Pennsylvania, USA

Correspondence: Dr Maria T. Landi, Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 6120 Executive Blvd., EPS 7114, Bethesda, Maryland 20892-7236, USA. E-mail: landim@mail.nih.gov

Deceased.

Received 2 November 2007; Revised 1 February 2008; Accepted 9 February 2008; Published online 27 March 2008.

Abstract

Melanocortin-1 receptor (MC1R) variants have been associated with BRAF (v-raf murine sarcoma viral oncogene homolog B1) mutations in non-CSD (chronic solar-damaged) melanomas in an Italian and an American population. We studied an independent Italian population of 330 subjects (165 melanoma patients and 165 controls) to verify and estimate the magnitude of this association and to explore possible effect modifiers. We sequenced MC1R in all subjects and exon 15 of BRAF in 92/165 melanoma patients. Patients with MC1R variants had a high risk of carrying BRAF mutations in melanomas (odds ratio (OR)=7.0, 95% confidence interval (CI)=2.1–23.8) that increased with the number of MC1R variants and variants associated with red hair color. Combining these subjects with the originally reported Italian population (513 subjects overall), MC1R variant carriers had a 5- to 15-fold increased risk of BRAF-mutant melanomas based on carrying one or two variants (P<0.0001, test for trend), and regardless of signs of chronic solar damage. In contrast, no association with BRAF-negative melanomas was found (OR=1.0, 95% CI=0.6–1.6). No characteristics of subjects or melanomas, including age, nevus count, pigmentation, and melanoma thickness or location on chronically or intermittently sun-exposed body sites, substantially modified this association, although results could be affected by the small numbers in some categories. This study confirms that the known MC1R–melanoma risk association is confined to subjects whose melanomas harbor BRAF mutations.