Department of Dermatology and Emory Skin Disease Research Core Center, Emory University School of Medicine, Atlana, Georgia, USA

Yazdi et al describe B-raf mutations in nevi with a particular histologic subtype, and find the frequency of mutation to be less frequent than initial reports of B-raf mutation (2003). B-raf is a member of the raf family of oncogenes, which includes A, B, and C-raf. These closely related genes stand in a pivotal section of the Ras-Map kinase pathway, in which raf proteins bind to membrane localized ras oncogenes and transmit signals to MAP kinase kinase (MEKK), which then transmits signals to MAP kinase (ERK, p42/44), which has a variety of downstream effects, including activation of AP-1, resulting in protumorigenic and proangiogenic effects, such as stimulation of vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs), and tissue factor (TF) (^{Cohen et al, 2002;Govindarajan et al, 2003}). After B-raf mutations were discovered to be the most prevalent mutations in human melanoma, they were described as occurring in high frequency in atypical nevi as well (^{Davies et al, 2002;Pollock et al, 2003}). This data shows that while B-raf mutations play an important role in human melanoma, they are by themselves neither necessary nor sufficient for the development of human melanoma. The data of Yazdi et al are consistent with these findings.

How do B-raf mutations fit into the current understanding of the multistep progression of melanomagenesis? Two genetic mutations are associated with atypical nevi, which are generally accepted to be precursors of melanoma. Many melanomas arise from atypical nevi, which have two genetic mutations associated with them. Hemizygosity of p16ink4a and activating mutations of B-raf have each been found in a proportion of nevi, and the data of Yazdi et al suggest that B-raf mutations have been found in a particular subset of nevi (^{Haluska and Hodi, 1998;Sviderskaya et al, 2002}). This is analogous to the finding of amplification of H-ras in a histologic subset of Spitz nevi (^{Bastian et al, 2000}).

Normal cells, including melanocytes, have defenses against oncogenic activation. Expression of mutant B-raf in normal melanocytes causes induction of a defensive enzyme, MAP kinase phosphatase, which as the name implies, results in dephosphorylation and inactivation of MAP kinase (^{Connor et al, 2003}). We have previously shown that activated MAP kinase is present in radial growth melanoma, but not atypical nevi, and that introduction of active MAP kinase kinase (MEKK) is sufficient to convert immortalized melanocytes into radial growth-like melanoma in mice. The finding of B-raf mutations, which can activate MAP kinase signaling in atypical nevi, suggests that loss of MAP kinase phosphatase is necessary to convert atypical nevi into melanoma, and allows us to predict that MAP kinase phosphatase is a tumor suppressor gene that is lost early in melanomagenesis. Efforts are currently underway in our laboratory to determine whether this is the case. A proposed pathway of melanoma progression is illustrated in Figure 1.

Figure 1.

Proposed role of MAP kinase phosphatase as a melanoma tumor suppressor.

Full figure and legend (11K)