BRAF gene mutations and cancer
The BRAF gene encodes a protein that plays a key role downstream of KRAS in the cell signaling pathway from the Epidermal Growth Factor Receptor (EGFR) that activates important cell functions, including cell proliferation and survival.
As reviewed by Garnett and Marais in 2004, BRAF gene mutations are found in many different cancers, the highest incidence being found in malignant melanoma (27%–70%), papillary thyroid cancer (36%–53%), colorectal cancer (5%–22%) and serous ovarian cancer (30%). Many different mutations in BRAF have been identified, but most mutations are extremely rare. The V600E mutation predominates, being found in 86% of BRAF mutations in cancer.
BRAF mutations in colorectal cancer
The presence of the activating V600E BRAF mutation in a tumour indicates poor prognosis in colorectal cancer, and possibly also in other cancer types such as thyroid and lung cancers. In colorectal cancer, the presence of the V600E BRAF mutation has also been associated with poor response to EGFR inhibitors.
BRAF mutations in melanoma
A large proportion of melanomas have a mutated BRAF gene. This has led to the development of melanoma therapies that specifically inhibit the mutant BRAF.
The US Food and Drug Administration (FDA) has approved Vemurafenib (Zelboraf®) for the treatment of BRAF V600 mutation positive metastatic melanoma. The data from a Phase III trial (BRIM3) showed that at 6 months, overall survival for patients treated with Vemurefenib was 84%, with 63% reduction in risk of death compared to chemotherapy (Dacarbazine). Vemurafenib also increased the progression-free survival by 74% compared to chemotherapy.
A trial evaluating Vemurafenib as combination treatment for metastatic melanoma on approximately 50 patients is also currently taking place. In this trial, Vemurafenib is combined with the MEK kinase inhibitor GDC-0973 to simultaneously target two key parts of the BRAF/MEK cancer signaling pathway.
BRAF mutation testing by Lab21
Lab21 provides a BRAF mutation testing service from its accredited clinical laboratory using a sensitive, CE-marked test method that can detect 1% BRAF mutation in 99% wild type background. The test only requires 3 sections of formalin-fixed, paraffin embedded (FFPE) tumour.
BRAF and KRAS mutation testing
KRAS is another important protein involved in the EGFR signalling pathway, where it acts upstream of BRAF. KRAS mutation testing is available from Lab21, and is easily combined with BRAF mutation testing.