BRAF

WKP

Definition: BRAF is a human gene that makes a protein called B-Raf. The gene is also referred to as proto-oncogene B-Raf and v-Raf murine sarcoma viral oncogene homolog B, while the protein is more formally known as serine/threonine-protein kinase B-Raf.

The B-Raf protein is involved in sending signals inside cells which are involved in directing cell growth.

Certain other inherited BRAF mutations cause birth defects.

Drugs that treat cancers driven by BRAF mutations have been developed. Two of these drugs, vemurafenib and dabrafenib are approved by FDA for treatment of late-stage melanoma.

Pathology

 BRAF-mutated thyroid carcinoma

• BRAF is an oncogene that is commonly mutated in both melanomas and papillary thyroid carcinomas (PTCs).
• Usually, mutations in the codons 600 or 601 lead to constitutive activity in the Ras-mitogen-activated protein kinase pathway and, recently, the BRAF deletion was described as a relevant risk factor for loco-regional PTC lymph node metastasis.
• For these reasons, BRAF mutations may be considered a key genetic factor for the metastatic progression of PTC and also for other tumors such as melanoma and colon cancer and a new BRAF-specific therapeutic strategy was already suggested.

 BRAF-mutated malignant melanoma

• BRAF somatic mutations are found in the majority of cutaneous malignant melanomas and subsets of other tumors.
• These mutations lead to constitutive activation of BRAF with increased downstream ERK (extracellular signal-regulated kinase) signaling; therefore, the development of RAF kinase inhibitors for targeted therapy is being actively pursued.

 somatic activating point mutations of the BRAF oncogene (predominant specific point mutation BRAF-V599E) in

• BRAF-mutated cutaneous malignant melanomas
• BRAF-mutated melanocytic nevi with the V600E BRAF mutation (17696195)
• BRAF-mutated thyroid papillary carcinoma (TPC)
• BRAF-mutated primary invasive melanomas (tandem BRAF mutations) (46%) (15140228)
• BRAF-mutated colorectal adenocarcinoma
• BRAF-mutated pulmonary adenocarcinoma
• BRAF-mutated non-Hodgkin lymphomas (2.4%)
• BRAF-mutated papillary thyroid carcinoma of ovary (struma ovarii) (17721188)

 BRAF fusions (MAPK pathway activation)

• AKAP9-BRAF fusion gene (15630448) in thyroid carcinomas
• BRAF-GIT2 fusion gene in pilocytic astrocytoma
• BRAF-TRIM24 fusion gene in melanoma
  • BRAF fusions define a new molecular subset of melanoma, potentially comprising 4% to 8% of "pan-negative" cases.
  • Their presence may explain an unexpected clinical response to MEK inhibitor therapy or assist in selecting patients for MEK-directed therapy.

 BRAF rarrangements

• myxoinflammatory fibroblastic sarcoma

 BRAF germline mutations

• in cardiofaciocutaneous syndrome (CFC syndrome)

Mutant proteins

 BRAF-V600E
 BRAF-K601E

Deletions

 BRAF deletions

Thyroid papillary carcinoma

Up to 60% of thyroid papillary carcinomas have mutations in the BRAF gene. However, follicular variant of papillary carcinoma has a much lower frequency of mutation.

Papillary carcinomas of the thyroid with papillary growth and areas of follicular growth have a high frequency of BRAF mutations. The BRAF mutational profile is identical in the follicular areas and in the conventional papillary growth areas.

Recently, the BRAF deletion was described as a relevant risk factor for loco-regional PTC lymph node metastasis.

BRAF mutations may be considered a key genetic factor for the metastatic progression of PTC and also for other tumors such as melanoma and colon cancer and a new BRAF-specific therapeutic strategy was already suggested.

Immunochemistry

 BRAF immunochemistry

• BRAF mutation-specific immunochemistry

Links

 The RAS-ERk signaling pathway at Biocarta
 The MAPKinases signaling pathway at Biocarta
 Animation of the organisation and function of the Ras-Raf-MEK-ERK pathway at Expert Reviews in Molecular Medicine
 kinase.uhnres.utoronto.ca

See also

 MAPK signaling pathways
 RAS/RAF/MAPK signaling pathway
 BRAF in thyroid tumors

References

 Rapid multiplex real-time PCR by molecular beacons for different BRAF allele detection in papillary thyroid carcinoma. Orru G, Coghe F, Faa G, Pillai S, Manieli C, Montaldo C, Pilia F, Pichiri G, Piras V, Coni P. Diagn Mol Pathol. 2010 Mar;19(1):1-8. PMID: 20186005

 Rapid Multiplex Real-time PCR by Molecular Beacons for Different BRAF Allele Detection in Papillary Thyroid Carcinoma. Orru G, Coghe F, Faa G, Pillai S, Manieli C, Montaldo C, Pilia F, Pichiri G, Piras V, Coni P. Diagn Mol Pathol. 2010 Mar;19(1):1-8. PMID: 20186005

 BRAF mutational analysis in papillary carcinomas with mixed follicular and papillary growth patterns. Jakubowski M, Hunt JL. Am J Surg Pathol. 2009 Nov;33(11):1590-3. PMID: 19738460

 Beta-catenin Nuclear Labeling is a Common Feature of Sessile Serrated Adenomas and Correlates With Early Neoplastic Progression After BRAF Activation. Yachida S, Mudali S, Martin SA, Montgomery EA, Iacobuzio-Donahue CA. Am J Surg Pathol. 2009 Sep 9. PMID: 19745699

 Spittle C, Ward MR, Nathanson KL, Gimotty PA, Rappaport E, Brose MS, Medina A, Letrero R, Herlyn M, Edwards RH. Application of a BRAF pyrosequencing assay for mutation detection and copy number analysis in malignant melanoma. J Mol Diagn. 2007 Sep;9(4):464-71. PMID: 17690212

 Schmidt J, Derr V, Heinrich MC, Crum CP, Fletcher JA, Corless CL, Nose V. BRAF in papillary thyroid carcinoma of ovary (struma ovarii). Am J Surg Pathol. 2007 Sep;31(9):1337-43. PMID: 17721188

 Bloethner S, Snellman E, Bermejo JL, Hiripi E, Gast A, Thirumaran RK, Wellenreuther R, Hemminki K, Kumar R. Differential gene expression in melanocytic nevi with the V600E BRAF mutation. Genes Chromosomes Cancer. 2007 Aug 15; PMID: 17696195

 Weisenberger DJ, Siegmund KD, Campan M, Young J, Long TI, Faasse MA, Kang GH, Widschwendter M, Weener D, Buchanan D, Koh H, Simms L, Barker M, Leggett B, Levine J, Kim M, French AJ, Thibodeau SN, Jass J, Haile R, Laird PW. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet. 2006 Jul;38(7):787-93. PMID: 16804544

 Dibb NJ, Dilworth SM, Mol CD. Switching on kinases: oncogenic activation of BRAF and the PDGFR family. Nat Rev Cancer. 2004 Sep;4(9):718-27. PMID: 15343278

 Niihori T, Aoki Y, Narumi Y, Neri G, Cave H, Verloes A, Okamoto N, Hennekam RC, Gillessen-Kaesbach G, Wieczorek D, Kavamura MI, Kurosawa K, Ohashi H, Wilson L, Heron D, Bonneau D, Corona G, Kaname T, Naritomi K, Baumann C, Matsumoto N, Kato K, Kure S, Matsubara Y. Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nat Genet. 2006 Feb 12; PMID: 16474404