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NRAS and BRAF Mutations Arise Early during Melanoma Pathogenesis and Are Preserved throughout Tumor Progression

Katarina Omholt ; Anton Platz ; Lena Kanter ; Ulrik Ringborg ; Johan Hansson

Clinical Cancer Research, 2003-12-15, Vol.9 (17), p.6483-6488 [Peer Reviewed Journal]

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  • Title:
    NRAS and BRAF Mutations Arise Early during Melanoma Pathogenesis and Are Preserved throughout Tumor Progression
  • Author: Katarina Omholt ; Anton Platz ; Lena Kanter ; Ulrik Ringborg ; Johan Hansson
  • Subjects: Melanoma - metabolism ; Proto-Oncogene Proteins c-raf - genetics ; Exons ; Humans ; Middle Aged ; Male ; Treatment Outcome ; Disease Progression ; MAP Kinase Signaling System ; Polymorphism, Single-Stranded Conformational ; DNA - chemistry ; Neoplasm Metastasis ; Codon ; DNA Mutational Analysis ; Adult ; Female ; Aged ; Mutation ; Genes, ras ; Proto-Oncogene Proteins B-raf ; Index Medicus
  • Is Part Of: Clinical Cancer Research, 2003-12-15, Vol.9 (17), p.6483-6488
  • Description: Purpose: 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. Experimental Design: 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.
  • Publisher: United States: American Association for Cancer Research
  • Language: English
  • Identifier: ISSN: 1078-0432
    EISSN: 1557-3265
    PMID: 14695152
  • Source: © ProQuest LLC All rights reserved

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