BRAF gene mutation analysis
BRAF gene encodes a serine/threonine kinase that functions within the Ras-Raf-MEK-MAPK pathway, which connects extracellular signals to transcriptional regulation. Activating mutations of BRAF are found in colorectal cancers (CRCs), melanomas, ovarian tumors, lung and thyroid cancers. The most frequent BRAF mutation is c.1799T>A (p.V600E), this mutation predisposes to apoptosis inhibition, increases invasiveness, and occurs during carcinogenesis.
Indications for mutation analysis:
- BRAF mutation can be utilized to identify sporadic MSI-H colorectal cancer cases and exclude them from germline mismatch repair gene testing. BRAF p.V600E mutation accounts for over 90% of BRAF mutations in colorectal cancer and is found in 30–80% of sporadic MSI-H colorectal cancer cases. This mutation is extremely rare in tumours associated with Lynch syndrome. The presence of the BRAF p.V600E mutation is strongly associated with sporadic CRCs that exhibit MSI due to somatic inactivation of MLH1 protein expression. If either the BRAF p.V600E mutation or MLH1 promoter methylation is found in a MSI-H tumor, then the tumor is probably sporadic and further testing for Lynch syndrome may not be warranted.
- BRAF mutation is an independent predictor for colorectal cancer patients’ responsiveness to EGFR inhibitors. BRAF mutations cause resistance to anti-epidermal growth factor receptor therapy in colorectal cancer patients, therefore BRAF status is a useful biomarker for selecting patients suitable for anti-EGFR treatment.
- BRAF mutation can be used to guide therapy for melanoma patients. BRAF mutations have been detected in 70% of primary melanomas. BRAF V600E kinase inhibitors are available for melanoma treatment, but their use is limited to patients with metastatic melanoma with a demonstrated BRAF p.V600E mutation.