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No Evidence for BRAF as a Melanoma/Nevus Susceptibility Gene

¹ Genetic Epidemiology Division, Cancer Research UK and ² Cancer Research UK Mutation Detection Facility, St. James's University Hospital, Leeds; ³ Section of Epidemiology, Institute of Cancer Research, Sutton; and ⁴ Department of Epidemiology and Public Health, London School of Hygiene and Tropical Medicine, London, United Kingdom

Requests for reprints: Julia A. Newton Bishop, Genetic Epidemiology Division, Cancer Research UK, Cancer Genetics Building, St. James's University Hospital, Beckett Street, Leeds, LS9 7TF, United Kingdom. Phone: 44-113-206-4668; Fax: 44-113-234-0183. E-mail: j.newton-bishop{at}cancer.org.uk

Somatic mutations of BRAF have been identified in both melanoma tumors and benign nevi. Germ line mutations in BRAF have not been identified as causal in families predisposed to melanoma. However, a recent study suggested that a BRAF haplotype was associated with risk of sporadic melanoma in men. Polymorphisms or other variants in the BRAF gene may therefore act as candidate low-penetrance genes for nevus/melanoma susceptibility. We hypothesized that promoter variants would be the most likely candidates for determinants of risk. Using denaturing high-pressure liquid chromatography and sequencing, we screened peripheral blood DNA from 184 familial melanoma cases for BRAF promoter variants. We identified a promoter insertion/deletion in linkage disequilibrium with the previously described BRAF polymorphism in intron 11 (rs1639679) reported to be associated with melanoma susceptibility in males. We therefore investigated the contribution of this BRAF polymorphism to melanoma susceptibility in 581 consecutively recruited incident cases, 258 incident cases in a study of late relapse, 673 female general practitioner controls, and the 184 familial cases. We found no statistically significant difference in either genotype or allele frequencies between cases and controls overall or between male and female cases for the BRAF polymorphism in the two incident case series. Our results therefore suggest that the BRAF polymorphism is not significantly associated with melanoma and the promoter insertion/deletion linked with the polymorphism is not a causal variant. In addition, we found that there was no association between the BRAF genotype and mean total number of banal or atypical nevi in either the cases or controls.

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