Determinants of BRAF mutations in primary melanomas

• Published in: JNCI : Journal of the National Cancer Institute Vol. 95; no. 24; pp. 1878 - 1880
• Main Authors: MALDONADO, Janet L, FRIDLYAND, Jane, PATEL, Hetal, JAIN, Ajay N, BUSAM, Klaus, KAGESHITA, Toshiro, ONO, Tomomichi, ALBERTSON, Donna G, PINKEL, Dan, BASTIAN, Boris C
• Format: Journal Article
• Language: English
• Published: Cary, NC Oxford University Press 17.12.2003; Oxford Publishing Limited (England)
• Subjects: Adult; Aged; Biological and medical sciences; Cancer; Cohort Studies; Dermatology; Female; Humans; Male; Medical sciences; Melanoma - etiology; Melanoma - genetics; Middle Aged; Mutation; Neoplasm Invasiveness; Oncogene Proteins - genetics; Proteins; Proto-Oncogene Proteins B-raf; Skin Neoplasms - etiology; Skin Neoplasms - genetics; Sunlight - adverse effects; Tumors of the skin and soft tissue. Premalignant lesions; Human; Skin disease; Ultraviolet radiation; Cancerology; C-Onc gene; Malignant melanoma; Genetics; Malignant tumor; Mutation; Solar radiation; Electromagnetic wave; Protooncogene
• ISSN: 0027-8874; 1460-2105
• DOI: 10.1093/jnci/djg123

The RAS/mitogen-activated protein kinase pathway sends external growth-promoting signals to the nucleus. BRAF, a critical serine/threonine kinase in this pathway, is frequently activated by somatic mutation in melanoma. Using a cohort of 115 patients with primary invasive melanomas, we show that BRAF mutations are statistically significantly more common in melanomas occurring on skin subject to intermittent sun exposure than elsewhere (23 of 43 patients; P<.001, two-sided Fisher's exact test). By contrast, BRAF mutations in melanomas on chronically sun-damaged skin (1 of 12 patients) and melanomas on skin relatively or completely unexposed to sun, such as palms, soles, subungual sites (6 of 39 patients), and mucosal membranes (2 of 21 patients) are rare. We found no association of mutation status with clinical outcome or with the presence of an associated melanocytic nevus. The mutated BRAF allele was frequently found at an elevated copy number, implicating BRAF as one of the factors driving selection for the frequent copy number increases of chromosome 7q in melanoma. In summary, the uneven distribution of BRAF mutations strongly suggests distinct genetic pathways leading to melanoma. The high mutation frequency in melanomas arising on intermittently sun-exposed skin suggests a complex causative role of such exposure that mandates further evaluation.