Disease progression and patient survival are significantly influenced by BRAF protein expression in primary melanoma

Background Mutation of BRAF is a prevalent event in melanoma. Despite much attention to the role of BRAF mutation in melanoma, the status of BRAF protein expression and its significance in melanoma progression are unknown. Objectives We investigated the BRAF expression level in different stages of melanocytic lesions and evaluated its correlation with clinicopathological features and patient survival. Methods Using tissue microarray, BRAF expression and its correlation with patient outcome was evaluated in 49 naevi samples and 370 patients with melanoma. We also evaluated the correlation of BRAF protein expression and V600E mutation using direct sequencing. Results Compared with naevi samples, BRAF expression was remarkably increased in primary melanomas and further increased in metastatic melanomas (P=18x10(-11)). High BRAF expression was significantly correlated with thicker tumours, ulceration and higher American Joint Committee on Cancer stages (P=15x10(-7), 15x10(-5) and 36x10(-13), respectively). In cases of primary melanoma, patients with high BRAF expression had significantly worse overall (P=0009) and disease-specific 5-year survival (P=0007). While there was a trend for higher prevalence of BRAF V600E mutation in patients with high BRAF protein expression, no significant correlation was observed between protein expression and BRAF mutation. Furthermore, univariate Cox regression analysis confirmed high BRAF protein expression as a strong risk factor for poor patient survival in primary melanoma [hazard ratio (HR) 208 for overall survival; HR 239 for disease-specific survival]. Conclusions Our data demonstrate that BRAF protein expression is significantly increased during melanoma progression. In addition, we revealed a novel prognostic value for BRAF protein expression in primary melanoma as it is significantly correlated with poor patient survival.