BRAF Gene Mutation Analysis

Medical Test

B-RAF is an oncogene belonging to the RAF family of serine–threonine-specific protein kinases, downstream of the epidermal growth factor receptor (EGFR) and the RAS family of small G-proteins (KRAS, HRAS, and NRAS) in the MAPK pathway. More than 30 mutations of the BRAF gene associated with human cancers have been identified. These mutations make the B-RRAF oncogene active, continuously sending signal downstream to the MAPK pathway, which then results in cell proliferation. The most common mutation is the missense mutation in codon 600 of exon 15 located on chromosome 7. BRAF mutations are most often found in melanoma (80%), colorectal cancer (5%), lung cancer (3%), ovarian cancer, and thyroid gland cancer. They are also found in lower prevalence in some other cancers such as acute myeloid leukemia, glioma, sarcomas, breast cancer, and hepatoma. More than 90% of mutations are the V600E (1799T>A) mutation. Recent studies have shown that metastatic colorectal cancer patients with this BRAF mutation do not have a strong response to anti-EGFR therapies such as cetuximab and panitumumab. This assay detects any amino acid change that has an A nucleotide at position 1799 in exon 15 of the BRAF gene regardless of any other common changes (could detect V600E/V600K/V600D), allowing identification of patients who are likely to benefit from such treatment.
The presence of somatic mutation in the B-RAF gene product, located downstream of EGFR signaling, has been shown to serve as a biomarker for poor prognosis and poor response to anti-EGFR cancer therapy in cancer patients.
Treatment of certain types of cancer with drugs targeted specifically at the EGFR receptor work only if there is no mutation of the EGFR pathway, which incldes BRAF. Therefore, before starting such therapy, analysis for EGFR family mutations is required. In fact, insurance companies do require this. Also BRAF is related to microsatellite instability status such that BRAF V600E positivity is unlikely to be a MLH1 mutant. In thyroid papillary carcinoma, BRAF mutation results in an aggressive phenotype so that knowledge of this status aids in treatment planning and recurrence risk assessment. 30 - 40% of papillary thyroid cancers are BRAF mutation positive. Treatment with MEK inhibitors may be useful in this group. About 35-45% of melanomas are BRAF muatation positive and this mutation is present in non-malignant nevi so that early detection may be possible. Melanomas with BRAF mutation are also sensitive to MEK inhibitors. 10-20% of ovarian cancers are positive for either BRAF or KRAS mutation, mostly low grade non-serous types.