BRAF

BRAF (v-Raf murine sarcoma viral oncogene homolog B) encodes a cytoplasmic serine/threonine kinase that functions downstream of RAS in the MAPK/ERK signaling cascade, which transduces extracellular growth factor signals to promote cell proliferation, differentiation, and survival. Normally, RAS activation recruits RAF (ARAF, BRAF, or CRAF) to the cell membrane, triggering a phosphorylation cascade: RAF → MEK → ERK, ultimately affecting gene transcription involved in cell cycle progression.

The most common BRAF mutation, V600E (valine to glutamate substitution at codon 600), occurs in the kinase domain and results in constitutive, RAS-independent activation of the MAPK pathway, leading to unchecked cellular proliferation. This mutation is found in approximately 50% of melanomas, 100% of hairy cell leukemias, and a significant proportion of papillary thyroid carcinomas, as well as in some colorectal cancers (associated with poorer prognosis and resistance to anti-EGFR therapy) and low-grade gliomas.

Clinically, BRAF V600E testing is essential for guiding targeted therapy. BRAF inhibitors (vemurafenib, dabrafenib) are used to treat BRAF-mutant melanoma, often combined with MEK inhibitors (trametinib, cobimetinib) to overcome resistance mechanisms (paradoxical MAPK pathway reactivation) and improve efficacy. In hairy cell leukemia, vemurafenib has shown high response rates. BRAF mutation status also has prognostic implications in papillary thyroid cancer, where it correlates with more aggressive disease and higher recurrence risk.

For boards, know: BRAF V600E mutation, MAPK pathway position (RAS-RAF-MEK-ERK), associated malignancies (melanoma, hairy cell leukemia, papillary thyroid cancer), and the mechanism/names of targeted therapies (vemurafenib, dabrafenib ending in '-fenib'; trametinib as MEK inhibitor).