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Molecular Oncolgy, Markers, Clinical Correlates |
Department of Biosciences, Karolinska Institute, Novum, 141 57 Huddinge, Sweden [R. K., S. A., K. C., K. H.]; Division of Molecular Genetic Epidemiology, German Cancer Research Center, 69120 Heidelberg, Germany [R. K., K. H.]; Department of Oncology and Radiotherapy, University of Turku, 20520 Turku, Finland [I. S., S. P.]; and Department of Oncology, 00290 Helsinki University Central Hospital, Helsinki, Finland [M. H-K.]
Purpose: The RAS-RAF-mitogen-activated protein kinase pathways mediate the cellular response to growth signals. In melanocytes, BRAF is involved in cAMP-dependent growth signals. Recently, activating mutations in the BRAF gene, were reported in a large proportion of melanomas. We have studied mutations in the BRAF gene and their association with clinical parameters.
Experimental Design: We analyzed exons 1, 11, and 15 of the BRAF gene and exons 1 and 2 of the N-ras gene for mutations in 38 metastatic melanomas by PCR-single-strand conformation polymorphism and direct sequencing. Kaplan-Meier survival and multivariate analyses were used to correlate mutations with various clinical parameters.
Results: Mutations in exon 15 of the BRAF gene were detected in 26 (68%) melanomas. In 25 cases, mutation involved the "hot spot" codon 6002of the BRAF gene. Three melanomas without a BRAF mutation carried amino acid substituting base changes at codon 61 of the N-ras gene. In a multivariate proportional hazard (Cox) model, BRAF mutation, along with the stage of metastatic melanomas, showed a statistically significant hazard ratio of 2.16 (95% confidence interval 1.02–4.59; 
2 for the model 6.94, degrees of freedom 2, P = 0.03) for diminished duration of response to the treatment. In a Kaplan-Meier survival model, cases with BRAF mutation showed longer disease-free survival (median of 12 months) than cases without mutation (median of 5 months), although this association was not statistically significant (Log-rank test P = 0.13).
Conclusions: Our results, besides confirming the high frequency of BRAF mutations in metastatic melanomas, also underline the potential importance of these mutations in disease outcome.
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