title: Number of nevi and early-life ambient UV exposure are associated with BRAF-mutant melanoma.
abstract: Malignant melanomas often contain BRAF or NRAS mutations, but the relationship of these mutations to ambient UV exposure in combination with phenotypic characteristics is unknown. In a population-based case series from North Carolina, 214 first primary invasive melanoma patients in the year 2000 were interviewed regarding their risk factors. Ambient solar UV exposures were estimated using residential histories and a satellite-based model. Cases were grouped on the basis of BRAF and NRAS somatic mutations, determined using single-strand conformation polymorphism analysis and radiolabeled DNA sequencing, and the risk profiles of these groups were compared. Mutually exclusive BRAF-mutant and NRAS-mutant cases occurred at frequencies of 43.0% and 13.6% with mean ages at diagnosis of 47.3 and 62.1 years, respectively. Tumors from patients with >14 back nevi were more likely to harbor either a BRAF mutation [age-adjusted odds ratio (OR), 3.2; 95% confidence interval (95% CI), 1.4-7.0] or an NRAS mutation (age-adjusted OR, 1.7; 95% CI, 0.6-4.8) compared with patients with 0 to 4 back nevi. However, BRAF-mutant and NRAS-mutant tumors were distinctive in that BRAF-mutant tumors were characteristic of patients with high early-life ambient UV exposure (adjusted OR, 2.6; 95% CI, 1.2-5.3). When ambient UV irradiance was analyzed by decadal age, high exposure at ages 0 to 20 years was associated with BRAF-mutant cases, whereas high exposure at ages 50 and 60 years was characteristic of NRAS-mutant cases. Our results suggest that although nevus propensity is important for the occurrence of both BRAF and NRAS-mutant melanomas, ambient UV irradiance influences risk differently based on the age of exposure. The association of BRAF mutations with early-life UV exposure provides evidence in support of childhood sun protection for melanoma prevention.
authors.affiliation: Department of Dermatology, University of North Carolina, Chapel Hill, NC 27599, USA. nthomas@med.unc.edu
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Thomas
authors.forename: Sharon N
authors.initials: SN
authors.lastname: Edmiston
authors.forename: Audrey
authors.initials: A
authors.lastname: Alexander
authors.forename: Robert C
authors.initials: RC
authors.lastname: Millikan
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Groben
authors.forename: Honglin
authors.initials: H
authors.lastname: Hao
authors.forename: Dawn
authors.initials: D
authors.lastname: Tolbert
authors.forename: Marianne
authors.initials: M
authors.lastname: Berwick
authors.forename: Klaus
authors.initials: K
authors.lastname: Busam
authors.forename: Colin B
authors.initials: CB
authors.lastname: Begg
authors.forename: Dianne
authors.initials: D
authors.lastname: Mattingly
authors.forename: David W
authors.initials: DW
authors.lastname: Ollila
authors.forename: Chiu Kit
authors.initials: CK
authors.lastname: Tse
authors.forename: Amanda
authors.initials: A
authors.lastname: Hummer
authors.forename: Julia
authors.initials: J
authors.lastname: Lee-Taylor
authors.forename: Kathleen
authors.initials: K
authors.lastname: Conway
mesh_terms: D016001:Confidence Intervals; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis / Q000737:chemistry / Q000235:genetics; D005260:Female; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D008297:Male; D008545:Melanoma / Q000453:epidemiology* / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D009506:Nevus / Q000473:pathology*; D009657:North Carolina / Q000453:epidemiology; D016017:Odds Ratio; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D012878:Skin Neoplasms / Q000453:epidemiology* / Q000235:genetics; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: D004273:DNA, Neoplasm; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf