BRAF mutations in metastatic melanoma: a possible association with clinical outcome.
OBJECTIVE
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.


METHODS
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 600(2)of 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; chi(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.
Kumar
Rajiv
R
Department of Biosciences, Karolinska Institute, Novum, 141 57 Huddinge, Sweden. rajiv.kumar@cnt.ki.se
Angelini
Sabrina
S
Czene
Kamila
K
Sauroja
Ilari
I
Hahka-Kemppinen
Marjo
M
Pyrhönen
Seppo
S
Hemminki
Kari
K
D000328:Adult; D000368:Aged; D001483:Base Sequence; D005091:Exons; D005260:Female; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000401:mortality; D008875:Middle Aged; D008969:Molecular Sequence Data; D015999:Multivariate Analysis; D009154:Mutation; D009362:Neoplasm Metastasis; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D016016:Proportional Hazards Models; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics*; D013997:Time Factors; D016896:Treatment Outcome
C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf