BRAF Heterogeneity in Melanoma

In the era of molecular targeted therapy, the accurate detection of BRAF mutation in melanoma has become increasingly important. With the advances of molecular analyses and immunohistochemistry, the presence of BRAF mutational heterogeneity in melanoma has been widely recognized. Although most patients with melanoma have a homogeneous BRAF mutation status because the BRAF mutation occurs at an early stage of melanoma development and acts as a driver gene mutation, BRAF mutational heterogeneity does exist, among different tumor sites of a single patient (intertumor heterogeneity) and/or even within a single tumor (intratumor heterogeneity). To summarize the published reports, about 10% of melanoma patients may show intertumorally discordant BRAF status and about 15% of BRAF-mutated melanomas may have intratumor BRAF heterogeneity, although the reported results vary strikingly among the studies and methods used. Considering the BRAF heterogeneity of melanoma, a single biopsy from a single tumor may not be sufficient to uncover the entire BRAF status of a patient. Multiple samples from different sites may be preferable to assess the indication of BRAF/MEK inhibitors, as recommended by the current clinical guidelines. The impact of BRAF heterogeneity on patient survival or the response to treatment with BRAF/MEK inhibitors is an interesting issue, but requires further investigation.