The BRAF proto-oncogene works by sending signals inside cells responsible for cell growth. It can become an oncogene from mutations or an increase in expression.
The BRAF gene encodes a protein that is known as serine/threonine-protein kinase. This protein is a kinase enzyme that phosphorylates the -OH groups of serine or threonine (which have similar side-chains). It mediates signal transduction from Ras to MEK in the MAPK/ERK signaling pathway resulting in cell division, proliferation, and differentiation.
The most frequent mutation of BRAF is a valine to glutamic acid substitution at codon 600 (V600E). This mutation has been found in more than 60% of melanomas, and 7-8% of other cancers.
Melanoma is the 5th most common cancer among men and 6th among women. About half of all melanomas have BRAF mutations. Advanced melanoma with a mutation in BRAF has a three-fold increased risk of death compared with melanoma without BRAF mutations.
Changes of Ras–RAF kinase pathway by BRAF mutation may contribute to non-Hodgkin lymphoma carcinogenesis. BRAF inhibitors can be used for this disease.
BRAF mutations are found in around 45-50% of all papillary thyroid cancers. Higher recurrence rates, extrathyroidal extension, lymph node metastases, and worse survival are associated with this mutation. BRAFV600E-positive advanced RAI-refractory thyroid cancer can be treated with vemurafenib. Dabrafenib is used for BRAFV600E mutated metastatic papillary thyroid carcinoma.
The BRAFV600E mutation is seen in 90% to 100% of hairy cell leukemia (HCL) patients. This mutation is a potential therapeutic target, especially for HCL patients who do not respond well to initial therapy with purine analogs.
Dabrafenib is often co-administered with MEK inhibitors (eg, trametinib) which are used after surgery in patients with stage III melanoma.
Vemurafenib (brand name Zelboraf) is used to treat metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test or melanoma that cannot be treated with resection. This medication is not indicated for wild-type BRAF melanoma.
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