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BRAF and Melanoma

Identification of the BRAF gene pinpoints a new target for melanoma therapy.

Every so often, the cancer genetics community gets excited about the discovery of a gene that is found to be frequently mutated in a specific cancer. One such gene, BRAF, is selectively mutated in cutaneous melanoma. Investigators examined a panel of 15 cancer cell lines (6 breast cancers, 1 small-cell lung cancer, 6 non-small-cell lung cancers, 1 melanoma, and 1 mesothelioma) and found 3 missense mutations in the gene for the signal molecule, BRAF. Having found a relatively high frequency of mutations, the authors examined an additional 530 cancer cell lines, 43 (8%) of which harbored mutations in BRAF. Almost 60% of the melanoma cell lines (20 of 34 samples) had mutations in this gene. Moreover, all 43 probable oncogenic mutations were localized to exons 11 and 15.

The authors demonstrated the functional consequences of these mutations. The gene for RAS, a small G protein, is one of the most commonly mutated oncogenes in human cancer. BRAF is a protein kinase (an enzyme that adds phosphate groups to proteins to alter the substrate's function) that mediates a pathway of RAS signaling. Evidence supports a biochemical pathway in which RAS turns on BRAF, which in turn activates the mitogen-activated protein (MAP) kineases. The authors showed that mutations in BRAF lead to increased kinase activity, leaving the "growth" signal always turned on. Putting the mutant BRAF gene into nontumorigenic NIH-3T3 cells caused transformation and tumor formation in mice. Genes must pass these classic in vitro and in vivo tests to be deemed oncogenes.

Comment: This study brings oncogenes back into the cancer landscape. When the study of cancer genetics began, oncogenes were the genes isolated most often because of the availability of functional assays. In fact, the first isolated human oncogenes were the RAS family. With isolation of the retinoblastoma tumor suppressor gene, attention shifted to molecular studies of tumor suppressors. BRAF is an attractive oncogene target for therapy because it is relatively specific for melanoma and because the large class of protein kinase inhibitors has been relatively successful against cancer (e.g., STI571 directly affects chronic myelogenous leukemia). Specific inhibitors of BRAF are no doubt under development for melanoma treatment.

— Hensin Tsao, MD, PhD

Published in Journal Watch Dermatology July 16, 2002

Citation(s):

Davies H et al. Mutations of the BRAF gene in human cancer. Nature 2002 Jul; 417:949-54.

• Medline abstract (Free)