Anatomic Pathology: Molecular Pathology Diagnostics

1282) Which of the following statements is TRUE?

• 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.

Flaherty KT, Fisher DE: New strategies in metastatic melanoma: oncogene-defined taxonomy leads to therapeutic advances. Clin Cancer Res 2011;17:4922-4928. Epub 2011 Jun 13.

Van Raamsdonk CD, Bezrookove V, Green G, et al: Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 2009;457:599-602. Epub 2008 Dec 10.

Van Raamsdonk CD, Griewank KG, CrosbyMB, et al: Mutations in GNA11 in uveal melanoma. N Engl J Med 2010;363:2191-2199. Epub 2010 Nov 17.

* = Required 
* Note Title
* Note