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BRAF mutations in metastatic melanoma: a possible association with clinical outcome
Rajiv Kumar1, Sabrina Angelini, Kamila Czene
1Department of Biosciences, Karolinska Institute, Novum, 141 57 Huddinge, Sweden. rajiv.kumar@cnt.ki.se
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 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.
Insights
Activating BRAF mutations are frequent in metastatic melanomas and may impact treatment response. This study investigated BRAF mutations and their association with clinical outcomes in melanoma patients.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- The RAS-RAF-mitogen-activated protein kinase (MAPK) pathway regulates cellular responses to growth signals.
- BRAF gene mutations are frequently identified in melanoma, a common skin cancer.
- Understanding BRAF mutation status is crucial for predicting melanoma behavior and treatment efficacy.
Purpose of the Study:
- To investigate the frequency of BRAF gene mutations in metastatic melanoma.
- To analyze the association between BRAF mutations and clinical parameters, including disease outcome.
Main Methods:
- Analysis of BRAF gene exons 1, 11, and 15 for mutations in 38 metastatic melanoma samples.
- Utilized PCR-single-strand conformation polymorphism and direct sequencing for mutation detection.
- Employed Kaplan-Meier survival and multivariate (Cox) analyses to correlate mutations with clinical data.
Main Results:
- BRAF mutations were detected in 68% of melanomas, with most occurring at the common codon 600.
- BRAF mutation was a significant predictor of diminished duration of response to treatment in a multivariate model (HR=2.16, P=0.03).
- Melanoma cases with BRAF mutations showed a trend towards longer disease-free survival (12 vs. 5 months), though not statistically significant.
Conclusions:
- Confirms a high prevalence of BRAF mutations in metastatic melanomas.
- Highlights the potential clinical significance of BRAF mutations in influencing melanoma patient outcomes.
- Suggests BRAF mutation status as a relevant factor for disease prognosis and treatment strategy.