BRAF Gene Mutation in Humans

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What is the BRAF gene?

The full name of the BRAF gene is “v-raf murine sarcoma viral oncogene homolog B1.” This gene has other symbols and is also known as BRAF1, RAFB1, and B-RAF1. The protein encoded by this gene is a member of the raf/mil family of serine/threonine protein kinases.

In humans, the BRAF gene is located on the chromosome 7. It has conserved regions of RAF protein kinases including a putative ATP-binding site and a catalytic lysine (Sithanandam et al., 1990). It is expressed in various tissues including the brain, placenta, and testis.

This protein is involved in the regulation of the mitogen-activated protein (MAP) kinase / extracellular signal regulated kinase (ERK) signaling pathway. The signaling pathway is associated with cell division, cell differentiation, and secretion. It is activated in most human tumors.

BRAF mutations have been related to various health problems, such as the cardiofaciocutaneous syndrome. This syndrome may show symptoms such as mental retardation and heart defects, with an obvious facial appearance. Mutations in this gene have been associated with different kinds of cancer, such as lung cancer, colon cancer, thyroid cancer, melanoma, and non-Hodgkin lymphoma.

BRAF Mutations and Disease

Mutations in BRAF may result in the ERK activation, a common component in human cancers (Pratilas and Solit, 2007). All mutations of the gene have been found within the kinase domain (Davies et al., 2002). Specifically, more than 40 different kinase domain mutations have been observed in the BRAF gene. Somatic missense mutations of this gene have been discovered in about 66% of malignant melanomas. In other human cancers, the mutations may occur at lower frequencies. For example, missense mutations have been detected in about 8% of human tumors, especially in thyroid cancer and colon cancer (Pratilas and Solit, 2007).

One of the most commonly seen mutations of the BRAF gene is a single base-pair substitution at the codon number 600 (V600E), which is found in exon 15. It is observed in more than 80% of the mutation cases (Pratilas and Solit, 2007). This type of mutation may enhance the kinase activity for about 500-fold higher than the wild-type gene. The mutation can promote cell proliferation, an essential process in tumor growth.

Together with mutations of other genes, the BRAF gene mutation (V600E) plays a significant role in the formation of tumors including melanoma and colon cancer. For example, a study of 330 colorectal tumors found 32 mutations in the BRAF gene (Rajagopalan et al., 2002). Among the samples, 28 tumors had the V600E mutation. In another study of 78 papillary thyroid cancers, about 35.8% of them had the V600E mutation (Kimura et al., 2003).

BRAF Gene Mutation and Cancer Treatment

Investigation of the structure and functions of the BRAF gene may help us understand the process of cancer formation for the exploration of new therapeutic opportunities. Because the BRAF gene plays an important role in human cancers, it has been suggested as an important target for cancer treatment. Novel therapeutics that can inhibit the pathway with better selectivity for BRAF gene are currently under examination (Pratilas and Solit, 2007).


Davies, H., Bignell, G. R., et al. (2002) Mutations of the BRAF gene in human cancer. Nature 417, 949-954.

Kimura, E. T., Nikiforova, M. N., et al. (2003) High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res 63, 1454-1457.

Pratilas, C. A. and Solit, D. B. (2007) Therapeutic strategies for targeting BRAF in human cancer. Rev Recent Clin Trials 2, 121-134.

Rajagopalan, H., Bardelli, A., et al. (2002) Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 418, 934.

Sithanandam, G., Kolch, W., et al. (1990) Complete coding sequence of a human B-raf cDNA and detection of B-raf protein kinase with isozyme specific antibodies. Oncogene 5, 1775-1780.