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.
Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. BRAF. My Cancer
(Updated December 7).
Last Updated: December 7, 2015
BRAF in GIST
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).
Suggested Citation: Maki, R., V. Keedy. 2015. BRAF in GIST. My Cancer
Genome https://www.padiracinnovation.org/content/disease/gist/braf/ (Updated
Last Updated: June 18, 2015
No Mutation Detected in KIT, PDGFRA and BRAF in GIST
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
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.
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
Last Updated: October 21, 2014
My Cancer Genome has released its new and improved cancer clinical trials search tool on our
beta website. Please visit beta.padiracinnovation.org
to check it out!