Click here for more information on BRAF mutation in non-small cell lung cancer (NSCLC).
BRAF mutations occur early, and alone are sufficient to drive pre-melanoma nevi formation.3 As a key initiation event, mutated BRAF acts in concert with secondary mutations to drive progression, invasion, and metastases of melanoma.3-5 This reliance on mutated BRAF (also called oncogene) is a process called oncogene addiction.1,2
Watch Dr Reingard Dummer discuss the role of BRAF mutation in the development of melanoma
In melanoma, the rate of BRAF mutation varies by anatomic type (eg, cutaneous, mucosal, uveal, etc).6 BRAF mutations occur in approximately 50% of cutaneous melanomas, which represent the largest molecular subtype.6,7
Mutation of BRAF V600 leads to a constitutive activation of the MAPK pathway, stimulation of cellular growth, and inhibition of pro-apoptotic signals, thereby driving cellular proliferation in tumour cells.1 One specific BRAF mutation, the T1799A transversion mutation in exon 15, results in a single amino acid substitution of a valine (V) to glutamic acid (E) at amino acid position 600 (V600E).1 This mutation accounts for approximately 90% of all BRAF mutations in melanoma (see figure above), and enables BRAF to bypass typical regulatory mechanisms.1,7-9 Mutations at this site make BRAF more than 10 times as active compared with wild-type BRAF.1
Hyperactivation of, and oncogenic addiction to, mutant BRAF makes it a key biomarker and a prime target for therapeutic intervention with targeted small molecule inhibitors.1,9
Watch Dr Reingard Dummer examine the role of the MAP kinase pathway and mutated BRAF as an oncogenic driver of disease