Molecular markers
Melanoma mutations
BRAF

Author: Joshua Bradish, M.D. (see Authors page)
Editor: Liang Cheng, M.D.

Revised: 12 June 2018, last major update February 2014

Copyright: (c) 2014-2018, PathologyOutlines.com, Inc.

PubMed Search: BRAF[TI] melanoma mutation[TI] free full text[sb]

See also: Stains - BRAF
Cite this page: Bradish, J. BRAF. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/molecularpathBRAF.html. Accessed September 25th, 2018.
Definition / general
  • BRAF is the gene encoding the B-Raf enzyme, a serine / threonine kinase involved in cell replication within the MAP kinase pathway (J Transl Med 2012;10:85)
  • BRAF may either form a heterodimer or homodimer for activation
  • BRAF activation is enhanced by RAS
  • Inhibition normally comes from ERK
  • MEK is the only known substrate of BRAF and is activated through phosphorylation
Diagrams / tables

Images hosted on other servers:

MAPK and AKT pathways

Resistance diagram

Mutations
  • BRAF mutations are found in ~50% of all melanomas (N Engl J Med 2005;353:2135)
  • The most common mutation is V600E, accounting for ~80 - 90% of all BRAF mutations identified
  • Less common mutations include V600K (10 - 20%), V600R (up to 5%), K601E (< 1%), G469A (< 1%), D594G (< 1%), V600M (< 1%), V600 'E2' (< 1%), L597V (< 1%)
  • BRAF appears to be nearly mutually exclusive with NRAS and KIT mutations
  • Overall survival does not appear to be affected by different types of BRAF mutations
Associated findings
  • Age < 55 years has been the #1 predictor of BRAF mutations (PLoS Med 2008;5:e120, Clin Cancer Res 2012;18:3242)
  • Melanomas arising on nonchronically sun damaged skin, acquired nevi and nodal nevi also have an association with BRAF mutations
  • Older age, melanomas arising from chronically sun damaged skin, melanomas arising in an acral or mucosal site and congenital nevi are NOT associated with BRAF mutations
Associated histological findings
  • Larger, rounder and more pigmented melanocytes (PLoS Med 2008;5:e120)
  • Pagetoid scatter
  • Nest formation
  • Sharp demarcation from uninvolved adjacent epidermis / dermis
  • Thickened epidermis
  • Ulceration, tumor thickness and mitotic count have NOT been associated with BRAF mutations
Detection methods
  • Historically detected using Sanger sequencing (numerous truncated strands secondary to dideoxynucleoside truncation are run on a gel and sequence is determined by speed and fluorescent labeling)
  • Cobas 4800 (Roche) testing is touted as a superior method of detection for V600E mutations but only detects ~50% V600K mutations and even lower detection for lower frequency mutations (Arch Pathol Lab Med 2012;136:1385)
  • PCR kit (Qiagen) detects V600E, Ec, K, D and R
  • PCR and DNA melting curve analysis
Inhibitor therapy
  • All patients with unresectable stage III and IV are recommended to undergo BRAF mutation analysis
  • Vemurafenib and dabrafenib are ATP competitive and selective BRAF inhibitors which have a high affinity for mutated BRAF enzymes and a much lower affinity for wild type enzymes
  • BRAF inhibitors significantly improve both progression free survival and overall survival in patients with BRAF mutations (N Engl J Med 2012;366:707, N Engl J Med 2011;364:2507)
  • Approximately 50% of patients respond (only 5% of patients on dacarbazine respond, the only chemotherapeutic drug approved by the FDA)
  • Both a reduction in tumor size and a marked increase in tumor infiltrating CD4+ and CD8+ lymphocytes are seen (Clin Cancer Res 2012;18:1386)
  • No impact on overall immune response has been noted
  • Approximately 1/4 of patients on inhibitors develop classic cutaneous squamous cell carcinoma and squamous cell carcinoma, keratoacathoma type, thought to be due to paradoxical activation of RAS mutations within keratinocytes
  • Trametinib, a MEK inhibitor, has been shown to improve progression free survival and overall survival as well (N Engl J Med 2012;367:107)
Mechanisms of resistance
Emerging combination therapies
  • New combination therapies are being evaluated for preventing or overcoming BRAF inhibitor resistance (Proc Natl Acad Sci USA 2013;110:4015)
  • Both BRAF and MEK inhibitors as well as BRAF and mTOR inhibitors have been shown to overcome resistance in vitro
  • Cross resistance between BRAF and MEK inhibition has also been described and may be secondary to the specific form of resistance employed (J Invest Dermatol 2012;132:1850)