BRAF Gene

BRAF is the acronym for "B-rapidly accelerated fibrosarcoma". The BRAF gene ("proto-oncogene B-Raf" or also "v-Raf murine sarcoma viral oncogene homolog B1"), localized on gene locus 7q34, belongs to a class of human oncogenes. The BRAF gene encodes a cytoplasmic serine / threonine kinase of the same name consisting of 766 amino acids. This consists of three conserved domains (CR1-CR3) characteristic of members of the Raf kinase family.

The BRAF (B-rapidly accelerated fibrosarcoma protein) enzyme plays a key role in the regulation of the mitogen-activated protein kinase signal transduction pathway known as the RAS/MAPK pathway. BRAF is responsible for regulating growth signals for the cell. Cell maturation, cell movement (migration) and apoptosis of cells are further influenced via the RAS/MAPK pathway. The impulses via the RAS/MAPK signaling pathway are essential for normal development before birth and postnatal cell division and differentiation.

Mutations in the BRAF gene can lead to permanent activation of the RAS/MAPK pathway, contributing to carcinogenesis. In general, activating missense mutations in codon 600 have been described in various tumors. The most common form of V600 mutation is the V600E mutation, in which valine is exchanged for glutamic acid.

Other known but rarer mutations of codon 600 include:

• V600D: Valine -> aspartic acid
• V600K: Valine -> Lysine
• V600M: Valine -> methionine
• V600R: Valine -> Arginine

The BRAF gene (BRAF stands for "B-rapidly accelerated fibrosarcoma protein") encodes a protein localized on chromosome 7q34 that belongs to the RAF family of serine/threonine protein kinases. It belongs to a class of human oncogenes. The encoded protein, a cytoplasmic serine/threonine kinase of the same name consisting of 766 amino acids, plays a role in regulating the MAP kinase/ERK signaling pathway, which affects cell division, differentiation, and secretion. Mutations in this gene, most commonly the V600E mutation, are the most commonly identified cancer-causing mutations in melanoma and have also been identified in several other cancers, including non-Hodgkin's lymphoma, colorectal cancer, thyroid cancer, non-small cell lung cancer, hairy cell leukemia, and adenocarcinoma of the lung. Mutations in this gene are also associated with cardiofaciocutaneous syndrome, Noonan syndrome, and Costello syndrome, which have overlapping phenotypes. A pseudogene of this gene has been identified on the X chromosome.

Mutations in the BRAF gene can lead to permanent activation of the RAS/MAPK pathway, contributing to carcinogenesis. In general, activating missense mutations in codon 600 have been described in various tumors. The most common form of V600 mutation is the V600E mutation, in which valine is exchanged for glutamic acid.

Other known but rarer mutations of codon 600 include:

• V600D: valine -> aspartic acid
• V600K: Valine -> Lysine
• V600M: Valine -> methionine
• V600R: Valine -> Arginine

Somatic V600E mutations are detectable in: non-Hodgkin's lymphoma, colorectal carcinoma, melanoma, papillary thyroid carcinoma, non-small cell lung cancer (NSCLC), glioblastoma, pleomorphic xanthoastrocytoma, hairy cell leukemia. In glial brain tumors, BRAF mutations occur in approximately 8% of cases.

Acquired V600E mutations in inflammatory (?) diseases: Erdheim-Chester disease (Cives M et al. 2015).

Inherited mutations of BRAF lead to malformation syndromes, such as cardio-facio-cutaneous syndrome (CFC syndrome: heart defects, facial malformations and mental retardation).

Targeted inhibition of B-Raf is possible with BRAF inhibitors, which are now part of the established repertoire of oncological therapies for numerous tumours.

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2. Davies H et al (2002) Mutations of the BRAF gene in human cancer. Nature 417: 949-54.
3. Schindler G et al (2011) Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta neuropath 121:397-405.
4. Cives M et al (2015) Erdheim-Chester disease: a systematic review. Crit Rev Oncol Hematol 95:1-11.
5. Haroun F et al (2017) Erdheim-Chester Disease: Comprehensive Review of Molecular Profiling and Therapeutic Advances. Anticancer Res 37:2777-2783.