title: NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression.
abstract: OBJECTIVE
  Recently, it was reported that BRAF mutations are frequent in melanoma. Previously, we analyzed a large series of paired primary and metastatic melanomas for NRAS codon 61 mutations and showed that they arise early and are preserved during tumor progression. Here, we have screened the same tumor samples for BRAF mutations.
  
  
  METHODS
  Primary melanomas (n = 71) and corresponding metastases (n = 88) from 71 patients were screened for BRAF exon 11 and exon 15 mutations using single-strand conformational polymorphism and nucleotide sequence analysis
  
  
  RESULTS
  BRAF mutations were found in 42 of 71 patients (59%). Thirty-seven patients had mutations that lead to a Val599Glu change, whereas mutations resulting in Gly468Ser, Val599Arg, Val599Lys, and Lys600Glu changes were detected in one patient each. Furthermore, one patient had a 6-bp insertion between codons 598 and 599, encoding two threonine residues. In most cases, paired primary and metastatic lesions had the same BRAF genotype (i.e., mutations present in the primary tumors were preserved in the corresponding metastases, and mutations did not arise at the metastatic stage if they were not present in the primary lesion). Using laser-capture microdissection, BRAF mutations were found in the radial growth phase of the primary lesions. BRAF mutations occurred exclusively in tumors that were wild type for NRAS, and in total, 89% of the patients analyzed (63 of 71) had mutations in either of these two genes.
  
  
  CONCLUSIONS
  The Ras-Raf-mitogen-activated protein kinase/extracellular signal-regulated kinase-extracellular signal-regulated kinase signaling pathway is activated in the vast majority of melanomas. Activation occurs through either NRAS or BRAF mutations, both of which arise early during melanoma pathogenesis and are preserved throughout tumor progression.
authors.affiliation: Cancer Centre Karolinska, Department of Oncology-Pathology, Radiumhemmet, Karolinska Hospital and Institute, Stockholm, Sweden.
authors.forename: Katarina
authors.initials: K
authors.lastname: Omholt
authors.forename: Anton
authors.initials: A
authors.lastname: Platz
authors.forename: Lena
authors.initials: L
authors.lastname: Kanter
authors.forename: Ulrik
authors.initials: U
authors.lastname: Ringborg
authors.forename: Johan
authors.initials: J
authors.lastname: Hansson
mesh_terms: D000328:Adult; D000368:Aged; D003062:Codon; D004247:DNA / Q000737:chemistry; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005091:Exons; D005260:Female; D011905:Genes, ras; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D008545:Melanoma / Q000378:metabolism*; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D018807:Polymorphism, Single-Stranded Conformational; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D003062:Codon; D004247:DNA; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf