Diagnosis: Melanoma
• BRAF is one of the serine threonine kinase isoforms that activates MEK following RAS activation. Melanomas have activating mutations of the RAS pathway, most commonly BRAF (50%) and NRAS (20%). Approximately, 1% has an activating mutation of the KIT receptor tyrosine kinase upstream of NRAS.
• BRAF mutations are even more common among nevi; therefore, a BRAF mutation is NOT diagnostic of melanoma.
• BRAF mutations, however, are an important target for treatment with vemurafenib a BRAF inhibitor.
• Vemurafenib is selective for mutated BRAF, and will not inhibit the pathway in the absence of BRAF mutations.
• Greater than 90% of BRAF mutations in melanomas involve Valine600, and the vast majority of these are “V600E” (valine to glutamine) mutations resulting from a 1799T>A transversion.
• Uveal melanomas, blue nevi, and central nervous system melanocytic lesions activate the mitogen activated protein kinase (MAPK) pathway by activating mutations of the G protein alpha subunits, GNA11, and GNAQ.
