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Home > A. Molecular pathology > Variants-Mutants > BRAF-V600E


Tuesday 2 February 2010

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.

Neoplasms associated with BRAF-V600E mutations:

- histiocytic proliferations

- hairy cell leukemia-class (not in HCL-variant)
- papillary thyroid carcinoma
- colonic adenocarcinoma
- malignant melanoma
- metanephric adenoma of the kidney
- papillary craniopharyngioma
- pleomorphic xanthoastrocytoma
- ameloblastoma

BRAF-associated tumors

- BRAF-mutated melanoma
- BRAF-mutated thyroid papillary carcinoma (BRAF-associatedTPC)

  • BRAF V600E is specific for papillary carcinoma.
  • It is found in anaplastic thyroid carcinoma when it arises from papillary thyroid carcinoma.

- BRAF-mutated pediatric malignant astrocytomas (20068183)

  • BRAF(V600E) mutation seems to define a subset of malignant astrocytomas in children, in which there is frequent concomitant homozygous deletion of CDKN2A. (20068183)

- BRAF-mutated benign nodal nevi (19033861)

- BRAF-mutated hairy cell leukemia (HCL)

  • The somatically acquired V600E mutation of the BRAF gene has been recently described as a molecular marker of hairy cell leukemia (HCL).
  • BRAF-V600E mutation is present in all HCL patients and that, in combination with clinical and morphological features, represents a reliable molecular marker for this condition. (22072557)

- BRAF-mutated peripheral nerve sheath tumours. (23190154)
- BRAF-mutated craniopharyngioma

BRAF-V600E immunochemistry

- BRAFV600E in Colorectal Cancers

  • In colorectal carcinoma, the presence of the BRAFV600E mutation can be used to virtually exclude Lynch syndrome in mismatch repair-deficient tumors.
  • In mismatch repair-proficient tumors, BRAFV600E mutation assessed by molecular methods has been proposed as a poor prognostic factor.
  • BRAFV600E and mismatch repair assessment by immunohistochemistry can be used as a powerful predictor of all-cause survival. (24157612)
  • Immunohistochemistry Facilitates Universal Screening of Colorectal Cancers for Lynch Syndrome. (23797718)
  • BRAFV600E mutation in microsatellite-unstable (MSI) colorectal carcinomas (CRCs) virtually excludes Lynch syndrome (LS).
  • In microsatellite-stable (MSS) CRCs it predicts poor prognosis.
  • BRAF IHC is highly concordant with 2 commonly used PCR-based BRAFV600E assays.
  • It performed well in identifying MLH1 mutation carriers from the ACCFR and identified all cases of proven LS.
  • Reflex BRAFV600E and MMR IHC are simple cheap tests that facilitate universal LS screening and identify the poor prognosis of the BRAFV600E-mutant MSS CRC phenotype.
  • BRAFV600E immunohistochemistry in conjunction with mismatch repair status predicts survival in patients with colorectal cancer. (25153715)

BRAF-V600E and senescence (16079850)

Most normal mammalian cells have a finite lifespan, thought to constitute a protective mechanism against unlimited proliferation. This phenomenon, called senescence, is driven by telomere attrition, which triggers the induction of tumour suppressors including p16(INK4a).

In cultured cells, senescence can be elicited prematurely by oncogenes; however, whether such oncogene-induced senescence represents a physiological process has long been debated.

Human naevi (moles) are benign tumours of melanocytes that frequently harbour oncogenic mutations (predominantly V600E, where valine is substituted for glutamic acid) in BRAF, a protein kinase and downstream effector of Ras.

Nonetheless, naevi typically remain in a growth-arrested state for decades and only rarely progress into malignancy (melanoma).

This raises the question of whether naevi undergo BRAF(V600E)-induced senescence. Sustained BRAF(V600E) expression in human melanocytes induces cell cycle arrest, which is accompanied by the induction of both p16(INK4a) and senescence-associated acidic beta-galactosidase (SA-beta-Gal) activity, a commonly used senescence marker.

Congenital naevi are invariably positive for SA-beta-Gal, demonstrating the presence of this classical senescence-associated marker in a largely growth-arrested, neoplastic human lesion.

In growth-arrested melanocytes, both in vitro and in situ, there is a marked mosaic induction of p16(INK4a), suggesting that factors other than p16(INK4a) contribute to protection against BRAF(V600E)-driven proliferation.

Naevi do not appear to suffer from telomere attrition, arguing in favour of an active oncogene-driven senescence process, rather than a loss of replicative potential.

Thus, both in vitro and in vivo, BRAF(V600E)-expressing melanocytes display classical hallmarks of senescence, suggesting that oncogene-induced senescence represents a genuine protective physiological process. (16079850)


- BRAF-V600E mutant protein is specifically targeted by the drug PLX4032.

See also

- BRAF mutations

  • BRAF-V600E
  • BRAF-K601E
    - BRAF deletions
    - BRAF-associated tumors

Open References

- A Further Investigation of Combined Mismatch Repair and BRAFV600E Mutation Specific Immunohistochemistry as a Predictor of Overall Survival in Colorectal Carcinoma. Luey N, Toon CW, Sioson L, Clarkson A, Watson N, Cussigh C, Kedziora A, Pincott S, Pillinger S, Evans J, Percy J, Engel A, Schnitzler M, Gill AJ.
PLoS One. 2014 Aug 25;9(8):e106105. doi : 10.1371/journal.pone.0106105 eCollection 2014. PMID: 25153715 [Free]



- BRAFV600E Immunohistochemistry Facilitates Universal Screening of Colorectal Cancers for Lynch Syndrome.Toon CW, Walsh MD, Chou A, Capper D, Clarkson A, Sioson L, Clarke S, Mead S, Walters RJ, Clendenning M, Rosty C, Young JP, Win AK, Hopper JL, Crook A, von Deimling A, Jenkins MA, Buchanan DD, Gill AJ. Am J Surg Pathol. 2013 Jun 20. PMID: 23797718

- The role of BRAF V600 mutation in melanoma. Ascierto PA, Kirkwood JM, Grob JJ, Simeone E, Grimaldi AM, Maio M, Palmieri G, Testori A, Marincola FM, Mozzillo N. J Transl Med. 2012 Jul 9;10:85. doi : 10.1186/1479-5876-10-85 PMID: 22554099 [Free]

- BRAF V600E and KRAS G12S mutations in peripheral nerve sheath tumours. Serrano C, Simonetti S, Hernández-Losa J, Valverde C, Carrato C, Bagué S, Orellana R, Somoza R, Moliné T, Carles J, Huguet P, Romagosa C, Ramón Y Cajal S. Histopathology. 2012 Aug 31. PMID: 23190154

- Immunohistochemical Analysis of BRAFV600E Expression of Primary and Metastatic Melanoma and Comparison With Mutation Status and Melanocyte Differentiation Antigens of Metastatic Lesions. Busam KJ, Hedvat C, Pulitzer M, von Deimling A, Jungbluth AA. Am J Surg Pathol. 2012 Dec 1. PMID: 23211290

- Immunohistochemical detection of the BRAF V600E-mutated protein in papillary thyroid carcinoma. Koperek O, Kornauth C, Capper D, Berghoff AS, Asari R, Niederle B, von Deimling A, Birner P, Preusser M. Am J Surg Pathol. 2012 Jun;36(6):844-50. PMID: 22592144

- The BRAF V600E mutation in hairy cell leukemia and other mature B-cell neoplasms. Arcaini L, Zibellini S, Boveri E, Riboni R, Rattotti S, Varettoni M, Guerrera ML, Lucioni M, Tenore A, Merli M, Rizzi S, Morello L, Cavalloni C, Da Vià MC, Paulli M, Cazzola M. Blood. 2011 Nov 9. PMID: 22072557

- BRAF(V600E) Mutation Analysis of Thyroid Nodules Needle Aspirates in Relation to Their Ultrasongraphic Classification: A Potential Guide for Selection of Samples for Molecular Analysis. Nam SY, Han BK, Ko EY, Kang SS, Hahn SY, Hwang JY, Nam MY, Kim JW, Chung JH, Oh YL, Shin JH. Thyroid. 2010 Mar;20(3):273-9. PMID: 20187782

- Oncogenic BRAF mutation with CDKN2A inactivation is characteristic of a subset of pediatric malignant astrocytomas. Schiffman JD, Hodgson JG, VandenBerg SR, Flaherty P, Polley MY, Yu M, Fisher PG, Rowitch DH, Ford JM, Berger MS, Ji H, Gutmann DH, James CD. Cancer Res. 2010 Jan 15;70(2):512-9. PMID: 20068183

- Benign nodal nevi frequently harbor the activating V600E BRAF mutation. Taube JM, Begum S, Shi C, Eshleman JR, Westra WH. Am J Surg Pathol. 2009 Apr;33(4):568-71. PMID: 19033861

- B-Raf(V600E) cooperates with alternative spliced Rac1b to sustain colorectal cancer cell survival. Matos P, Oliveira C, Velho S, Gonçalves V, da Costa LT, Moyer MP, Seruca R, Jordan P. Gastroenterology. 2008 Sep;135(3):899-906. PMID: 18602919

- The histopathology of BRAF-V600E-mutated lung adenocarcinoma. Yousem SA, Nikiforova M, Nikiforov Y. Am J Surg Pathol. 2008 Sep;32(9):1317-21. PMID: 18636014

- Pyrosequencing analysis for detection of a BRAFV600E mutation in an FNAB specimen of thyroid nodules. Kim SK, Kim DL, Han HS, Kim WS, Kim SJ, Moon WJ, Oh SY, Hwang TS. Diagn Mol Pathol. 2008 Jun;17(2):118-25. PMID: 18382358

- Ichii-Nakato N, Takata M, Takayanagi S et al. High frequency of BRAFV600E mutation in acquired nevi and small congenital nevi, but low frequency of mutation in medium-sized congenital nevi. J. Invest. Dermatol. 2006; 126; 2111–2118.

- RASSF1A and NORE1A methylation and BRAFV600E mutations in thyroid tumors. Nakamura N, Carney JA, Jin L, Kajita S, Pallares J, Zhang H, Qian X, Sebo TJ, Erickson LA, Lloyd RV. Lab Invest. 2005 Sep;85(9):1065-75. PMID: 15980887

- BRAFE600-associated senescence-like cell cycle arrest of human naevi. Michaloglou C, Vredeveld LC, Soengas MS, Denoyelle C, Kuilman T, van der Horst CM, Majoor DM, Shay JW, Mooi WJ, Peeper DS. Nature. 2005 Aug 4;436(7051):720-4. PMID: 16079850