• What is BRAF?
  • BRAF in Ovarian Cancer
  • BRAF c.1790T>G (L597R)
  • 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.1790T>G (L597R) 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 L597R mutations in BRAF-mutated ovarian cancer 1.2% (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 timea

The L597R mutation results in an amino acid substitution at position 597 in BRAF, from a leucine (L) to an arginine (R). 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 Preclinical studies suggest that downstream signaling induced by L597Q, L597R, and L597S mutants may be blocked by the MEK inhibitor, trametinib (GSK1120212) and possibly the BRAF inhibitor, vemurafenib (Dahlman et al. 2012). Which class of drugs will be more effective in patients with L597 mutations is currently unknown. However, a patient with metastatic melanoma whose tumor harbored an L597S mutation responded to the MEK inhibitor, TAK-733 (Dahlman et al. 2012).

BRAF_L597R_new.png

Figure 1.
Schematic of BRAF L597R 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.1790T>G (L597R) Mutation in Ovarian Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/ovarian-cancer/braf/138/ (Updated August 7).

Last Updated: August 7, 2014

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