BRAF-V600E
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.
BRAF-associated tumors
melanoma
thyroid papillary carcinoma (TPC).
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#)
benign nodal nevi (#19033861#)
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#)
Treatment
BRAF-V600E mutant protein is specifically targeted by the drug PLX4032.
See also
BRAF mutations
- V600E
- K601E
BRAF deletions
BRAF-associated tumors
References
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#
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#
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#