title: Determinants of BRAF mutations in primary melanomas.
abstract: 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.
authors.affiliation: Department of Dermatology, University of California, San Francisco, San Francisco, CA 94115, USA.
authors.forename: Janet L
authors.initials: JL
authors.lastname: Maldonado
authors.forename: Jane
authors.initials: J
authors.lastname: Fridlyand
authors.forename: Hetal
authors.initials: H
authors.lastname: Patel
authors.forename: Ajay N
authors.initials: AN
authors.lastname: Jain
authors.forename: Klaus
authors.initials: K
authors.lastname: Busam
authors.forename: Toshiro
authors.initials: T
authors.lastname: Kageshita
authors.forename: Tomomichi
authors.initials: T
authors.lastname: Ono
authors.forename: Donna G
authors.initials: DG
authors.lastname: Albertson
authors.forename: Dan
authors.initials: D
authors.lastname: Pinkel
authors.forename: Boris C
authors.initials: BC
authors.lastname: Bastian
mesh_terms: D000328:Adult; D000368:Aged; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000209:etiology / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness; D015513:Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics*; D013472:Sunlight / Q000009:adverse effects
chemical_list: D015513:Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf