• What is BRAF?
  • BRAF in Ovarian Cancer
  • BRAF c.1799T>A (V600E)
  • Clinical Trials

BRAF

BRAF belongs to a family of serine-threonine protein kinases that includes ARAF, BRAF, and CRAF (RAF1). RAF kinases are central mediators in the MAP kinase signaling cascade and exert their effect predominantly through phosphorylation and activation of MEK. This occurs following the dimerization (hetero- or homo-) of the RAF molecules. As part of the MAP kinase pathway, RAF is involved in many cellular processes, including cell proliferation, differentiation, and transcriptional regulation.

Mutant BRAF has been implicated in the pathogenesis of several cancers, including melanoma, non-small cell lung cancer, colorectal cancer, papillary thyroid cancer, and ovarian cancer (Davies et al. 2002). Mutant BRAF has been observed in these cancers as well as glioma and gastrointestinal stromal tumor (GIST).

mapk-pk13.png

Figure 1. Schematic of the MAPK and PI3K pathways. Growth factor binding to receptor tyrosine kinase results in activation of the MAPK signaling pathway (RAS-RAF-MEK-ERK) and the PI3K pathway (PI3K-AKT-mTOR). The letter "K" within the schema denotes the tyrosine kinase domain.

Related Pathways

Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. BRAF. My Cancer Genome https://www.padiracinnovation.org/content/disease/ovarian-cancer/braf/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

BRAF in Ovarian Cancer

Somatic mutations in BRAF have been found in a fraction of ovarian cancers and are associated with Type I tumors (see Table). The most common variant is V600E in 95% of cases (COSMIC).

Table 1. Frequency of Somatic Gene Mutations in Epithelial Ovarian Cancer (EOC)

  EOC Overall Type I Type II
Gene Mutation   Low Grade Serous Clear Cell Endometrioid Mucinous High Grade Serous
BRAF 11% (Kurman and Shih 2011) 24–33% (Singer et al. 2003; Nakayama et al. 2006) 1% (Kuo et al. 2009) 24% (Singer et al. 2003) 50–75% (Gemignani et al. 2003) <1% (TCGA 2011)

Table 2. Frequencies of specific mutations.

Gene Exon Location Amino Acid Position Amino Acid Change Nucleotide Change Frequency Among BRAF-mutated Ovarian Cancer
BRAF 15 Kinase Domain L597 p.L597R c.1790T>G 1.2% (COSMIC)
K600 p.V600E c.1799T>A​ 91% (COSMIC)
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Contributors: Dineo Khabele, M.D.

Suggested Citation: Khabele, D. 2015. BRAF in Ovarian Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/ovarian-cancer/braf/ (Updated June 17).

Last Updated: June 17, 2015

BRAF c.1799T>A (V600E) Mutation in Ovarian Cancer

Properties
Location of mutation Kinase domain (exon 15)
Frequency of BRAF mutations in ovarian cancer 11% (Kurman and Shih 2011)
Frequency of V600E mutations in BRAF-mutated ovarian cancer 91% (COSMIC)
Implications for Targeted Therapeutics
Response to EGFR TKIs Unknown at this time (Haldar et al. 2007)
Response to anti-EGFR antibodies Unknown at this time (Haldar et al. 2007)
Response to BRAF inhibitors Unknown at this timea
Response to MEK inhibitors Unknown at this time

The V600E mutation results in an amino acid substitution at position 600 in BRAF, from a valine (V) to a glutamic acid (E). This mutation occurs within the kinase domain (Figure 1). Mutant BRAF proteins have increased kinase activity and are transforming in vitro (Davies et al. 2002).

a Clinical responses of patients harboring a BRAF V600E ovarian tumor-associated mutation to BRAF inhibitors are unknown at this time. However, a phase I trial of the BRAF inhibitor, vemurafenib (PLX4032), showed a >80% response rate in BRAF V600E positive melanoma (Flaherty et al. 2010). In the follow-up randomized phase III trial comparing vemurafenib to dacarbazine in previously untreated, metastatic melanoma with the BRAF V600E mutation, vemurafenib improved rates of overall survival and progression-free survival (Chapman et al. 2011). In addition, responses to this BRAF inhibitor have also been reported in BRAF V600E positive ovarian, thyroid, and rectal cancer (Flaherty et al. 2009).

BRAF_V600E_new.png

Figure 1.
Schematic of BRAF V600E mutation. Functional domains of BRAF are depicted. CR1: conserved regions 1. CR2: conserved region 2.  

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Contributors: Dineo Khabele, M.D.

Suggested Citation: Khabele, D. 2014. BRAF c.1799T>A (V600E) Mutation in Ovarian Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/ovarian-cancer/braf/54/ (Updated August 7).

Last Updated: August 7, 2014

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