title: Distinct patterns of DNA copy number alterations associate with BRAF mutations in melanomas and melanoma-derived cell lines.
abstract: A majority of malignant melanomas harbor an oncogenic mutation in either BRAF or NRAS. If BRAF and NRAS transform melanoma cells by a similar mechanism, then additional genetic aberrations would be similar (or random). Alternatively, distinct mutation-associated changes would suggest the existence of unique cooperating requirements for each mutation group. We first analyzed a panel of 52 melanoma cell lines (n = 35, 11, 6 for BRAF*, NRAS*, and BRAF/NRAS(wt/wt), respectively) by array-based comparative genomic hybridization for unique alterations that associate with each mutation subgroup. Subsequently, those DNA copy number changes that correlated with a mutation subgroup were used to predict the mutation status of an independent panel of 43 tumors (n = 17, 13, 13 for BRAF*, NRAS*, and BRAF/NRAS(wt/wt), respectively). BRAF mutant tumors were classified with a high rate of success (74.4%, P = 0.002), whereas NRAS mutants were not significantly distinguished from wild types (26/43, P = 0.12). Copy number gains of 7q32.1-36.3, 5p15.31, 8q21.11, and 8q24.11 were most strongly associated with BRAF* tumors and cell lines, as were losses of 11q24.2-24.3. BRAF* melanomas appear to be associated with a specific profile of DNA copy number aberrations that is distinct from those found in NRAS* and BRAF/NRAS(wt/wt) tumors. These findings suggest that although both BRAF and NRAS appear to function along the same signal transduction pathway, each may have different requirements for cooperating oncogenic events. The genetic loci that make up this profile may harbor therapeutic targets specific for tumors with BRAF mutations.
authors.affiliation: Translational Medicine Oncology, GlaxoSmithKline, King of Prussia, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Greshock
authors.forename: K
authors.initials: K
authors.lastname: Nathanson
authors.forename: A
authors.initials: A
authors.lastname: Medina
authors.forename: M R
authors.initials: MR
authors.lastname: Ward
authors.forename: M
authors.initials: M
authors.lastname: Herlyn
authors.forename: B L
authors.initials: BL
authors.lastname: Weber
authors.forename: T Z
authors.initials: TZ
authors.lastname: Zaks
mesh_terms: D045744:Cell Line, Tumor; D016009:Chi-Square Distribution; D002869:Chromosome Aberrations; D018628:Gene Dosage; D011905:Genes, ras; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D009154:Mutation; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D015398:Signal Transduction
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf