BRAF Mutation — Genetic Marker in Cancer

The BRAF gene encodes a serine/threonine-protein kinase that operates as an integral component of the MAPK/ERK signalling pathway. Under normal physiological conditions, this pathway transmits chemical signals from outside the cell to the cell nucleus, tightly orchestrating cellular proliferation, differentiation, and survival. Mutations in the BRAF gene disrupt this regulatory mechanism by locking the kinase enzyme into an active conformation, precipitating persistent, autonomous downstream signalling that promotes oncogenesis.

The vast majority of oncogenic BRAF mutations involve a specific amino acid substitution at position 600 of the protein chain, predominantly the V600E alteration, where valine is replaced by glutamic acid. Other less frequent variants include V600K and V600R. These mutations are typically somatic, meaning they are acquired in tumour cells during a person's lifetime rather than inherited from parents, and they act as primary oncogenic drivers in several distinct malignancies.

Knowing whether a cancer harbours a BRAF mutation directly shapes clinical decision-making. It serves as both a predictive and prognostic biomarker. Patients whose tumours test positive for a BRAF V600 mutation often qualify for targeted therapy combinations that block the hyperactive protein. These targeted treatments can shrink tumours rapidly and improve survival outcomes compared with traditional chemotherapy. Conversely, establishing the absence of a BRAF mutation prevents patients from receiving therapies that would not benefit them, avoiding unnecessary toxicity.

BRAF mutations are identified by analysing tumour tissue acquired via biopsy or surgical excision. Molecular diagnostic techniques, including next-generation sequencing (NGS), polymerase chain reaction (PCR) assays, and immunohistochemistry (IHC), detect the mutation reliably. When tissue biopsies are difficult to obtain or repeat, liquid biopsies that analyse circulating tumour DNA (ctDNA) from a blood sample may be utilised to detect BRAF status and monitor emergence of treatment resistance.

BRAF mutations are most renowned in cutaneous melanoma, occurring in roughly 40 to 50 percent of cases. They are also identified in approximately 8 to 10 percent of metastatic colorectal cancers, up to 5 percent of non-small cell lung cancers, and a significant proportion of papillary thyroid cancers. Additionally, BRAF mutations are found in rarer conditions such as hairy cell leukaemia, Langerhans cell histiocytosis, and certain paediatric brain tumours.

Tumours carrying BRAF V600 mutations are treated with BRAF inhibitors (such as dabrafenib, vemurafenib, or encorafenib), typically combined with MEK inhibitors (such as trametinib, cobimetinib, or binimetinib) to overcome resistance and enhance efficacy. In BRAF-mutant metastatic colorectal cancer, targeted combinations frequently pair a BRAF inhibitor with an anti-EGFR antibody like cetuximab. Common side effects of these targeted combinations include rash, pyrexia, fatigue, and joint pain.