• What is BRAF?
  • BRAF in GIST
  • BRAF No Mutation Detected
  • Clinical Trials


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).


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/gist/braf/?tab=0 (Updated December 7).

Last Updated: December 7, 2015


Somatic mutations in BRAF have been found in <1% of GIST (Agaimy et al. 2009), and are similar to those seen in melanoma. In particular, the most common BRAF mutations are missense mutations which introduce an amino acid substitution at valine 600, in particular V600E (valine to glutamic acid). The result of these mutations is enhanced BRAF kinase activity and increased phosphorylation of downstream targets, particularly MEK (Hubbard 2004).

As in melanoma, BRAF mutations in GIST are non-overlapping with other oncogenic mutations found in GIST (e.g., KIT or PDGFRA mutations). BRAF mutations appear to be associated with a high risk of malignancy and resistance to presently available KIT/PDGFRA tyrosine kinase inhibitors (Agaram et al. 2008).

Contributors: Robert G. Maki, M.D., Ph.D., FACP, Vicki Keedy, M.D., M.S.C.I.

Suggested Citation: Maki, R., V. Keedy. 2015. BRAF in GIST. My Cancer Genome https://www.padiracinnovation.org/content/disease/gist/braf/ (Updated June 18).

Last Updated: June 18, 2015

No Mutation Detected in KIT, PDGFRA and BRAF in GIST

Location of mutation N/A
Frequency of no mutations detected in KIT/PDGFRA/BRAF in GIST 12–15% (Heinrich et al. 2003)
Implications for Targeted Therapeutics
Response to imatinib Confers decreased sensitivity
Response to sunitinib Some evidence of activity
Response to sorafenib Some evidence of activity (Kindler et al. 2011)
Response to nilotinib Unknown at this time
Response to regorafenib Evidence of activity (Demetri et al. 2013)
Response to dasatinib Some evidence of activity (Schittenhelm et al. 2006; Trent et al. 2011)

GISTs with no detected mutations in KIT, PDGFRA, and BRAF were formerly referred to as wild type; more precisely, wild type refers to those GISTs that do not have mutations in KIT, PDGFRA, and BRAF. A significant proportion of GISTs without other mutations have mutations instead in genes encoding the protein succinate dehydrogenase (SDH), most commonly SDHB (Janeway et al. 2010​) or SDHA. Approximately half of people with no KIT, PDGFRA, and BRAF mutations detected in their metastatic GIST have stable disease for ≥ 6 months when treated with second line sunitinib (Heinrich et al. 2008). Furthermore, people who get worse despite imatinib and sunitinib for their metastatic GIST, regorafenib is useful, whether or not there are KIT, PDGFRA, and BRAF mutations (Demetri et al. 2013).

Of note, “no mutation detected” means that tumors were tested for one or more mutations in one or more genes and none of these specific mutations were detected. “No mutation detected” is sometimes referred to as “wild type.” However, these two terms do not refer to precisely the same thing. Strictly speaking, the mutation status should be qualified based on the testing method used. For example, if the testing only included amino acid V600 in BRAF and no mutation was detected, then the BRAF mutation status for that tumor would be "wild type at amino acid V600." Since we now know more about mutations in genes other than KIT, PDGFRA, and BRAF, the “wild type” terminology is out of date.

One year of adjuvant imatinib does not improve relapse free survival for people with GISTs that have no KIT, PDGFRA, and BRAF mutations, p=0.6 (Corless et al. 2010). For people with no KIT, PDGFRA, and BRAF mutations detected in GIST in the high-risk category (i.e., > 5 cm, > 5/50 HPF mitotic count), there may be some benefit of 3 years compared to 1 year of adjuvant imatinib; however, too few people were included to make a definitive recommendation, HR 0.41, p=0.1 (Joensuu et al. 2011). ​

Note that this page is cross-listed under KIT no mutation detected and PDGFRA no mutation detected in GIST.


Contributors: Robert G. Maki, M.D., Ph.D., FACP, Vicki Keedy, M.D., M.S.C.I.

Suggested Citation: Maki, R., V. Keedy. 2014. No Mutation Detected in KIT, PDGFRA and BRAF in GIST. My Cancer Genome https://www.padiracinnovation.org/content/disease/gist/braf/55/ (Updated October 21).

Last Updated: October 21, 2014

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