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GIST with a BRAF Mutation

Among the 10-15% of adult GISTs that are wildtype for KIT and PDGFRA (lacking mutations in these
genes), a small subset of GISTs are driven by mutations in the gene for BRAF.  Activated BRAF
protein transmits signaling through the MAPK pathway: RAS/RAF/MEK/ERK.  This is one of the
pathways activated by KIT and PDGFRA (among other receptors), but BRAF activates this path at a
later point in the signaling sequence without stimulation by KIT or PDGFRA.  The MAPK pathway is
involved in cell proliferation, migration, and survival.

Several studies have found BRAF mutations in GISTs.  Each study is summarized here, and the reference citations are listed at the bottom of the page.

Agaram et al (2008) first identified the mutation V600E in exon 15 of the BRAF gene in some adult wildtype GISTs.  This mutation affects the activation domain of the signaling molecule, and has been found in a wide variety of human cancers.  In the Agaram et al study, the BRAF V600E mutation was found in three patients, all 49-55 year-old females whose primary GISTs were located in the small bowel, and they had a high risk of malignancy.  BRAF mutations were not detected in any of the 15 pediatric and 5 young adult GIST samples examined in this study.

Agaimy et al. (2009)  detected the BRAF V600E mutation in 2 of 28 GISTs (7%) that were wildtype for KIT and PDGFRA. The two GISTs originated in the gastric body and the jejunum in two men (mean age, 76 years), were early-stage (< 5mm), and were discovered as incidental findings during resection for other reasons. Both tumors qualified as very low risk for aggressive behavior according to the NIH consensus criteria.  The authors concluded that BRAF V600E mutations are not by themselves associated with a high risk of malignancy.

Martinho et al (2009) examined samples from 26 wildtype GISTs and found the BRAF V600E mutation in one case (3.8%).  The patient with this mutation was a 71-year-old man who had an intermeidate-risk spindle-cell GIST originating from the small intestine.

Hostein et al (2010) searched for BRAF mutations among 70 wildtype GISTs and 251 GISTs with KIT or PDGFRA mutations.  None of the KIT- or PDGFRA-mutant GISTs showed BRAF mutations.  Nine of the 70 wildtype GISTs (13%) showed the BRAF V600E mutation, including 5 small intestinal tumors, 1 duodenal tumor, 2 gastric tumors,   and 1 peritoneal tumor.  Seven of the 9 were spindle-cell tumors, 2 showed mixed spindle + epithelioid cells, and 1 was epithelioid.  Three were high-risk, 3 intermediate-risk, 2 low-risk, and 1 undetermined for risk.  Activation of the MAPK pathway appeared equivalent in all GISTs regardless of mutation type. 

Daniels et al (2011) examined 87 GISTs without KIT or PDGFRA mutations and found the BRAF mutation V600E in 3 cases (3.5%).

In summary, BRAF mutation V600E has been found in 3-13% of wildtype GISTs (those without KIT or PDGFRA muations).  This genotype may be more common in non-gastric GISTs according to the small studies reported so far. 

Possible Treatment Options

Treatment with drugs to inhibit KIT and PDGFRA would be ineffective in controlling GISTs with mutant BRAF.  Sorafenib could potentially be a relevant drug for these tumors, as well as other drugs in clinical trials for other BRAF-driven cancers such as melanoma.  One drug that in 2011 gained FDA approval for BRAF-mutant melanoma is vemurafenib (brand name Zelboraf).

Falchook et al (2013) reported the first case study of treatment of a patient with a BRAF-mutant GIST using a BRAF inhibitor, dabrafenib.  Prior treatment with tyrosine kinase inhibitors and a MEK inhibitor had not been effective, but the patient acheived tumor response for 8 months using dabrafenib.
 

References

Agaimy A, Terracciano LM, Dirnhofer S, Tornillo L, Foerster A, Hartmann A, Bihl MP.
V600E BRAF mutations are alternative early molecular events in a subset of KIT/PDGFRA wild-type gastrointestinal stromal tumours.
J Clin Pathol. 2009 Jul;62(7):613-6.
PubMed PMID: 19561230.

Agaram NP, Wong GC, Guo T, Maki RG, Singer S, Dematteo RP, Besmer P, Antonescu CR.
Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors. Genes Chromosomes Cancer. 2008 Oct;47(10):853-9.
PubMed PMID: 18615679; PubMed Central PMCID: PMC2902874. (free access to full paper)

Daniels M, Lurkin I, Pauli R, Erbstösser E, Hildebrandt U, Hellwig K, Zschille U, Lüders P, Krüger G, Knolle J, Stengel B, Prall F, Hertel K, Lobeck H, Popp B, Theissig F, Wünsch P, Zwarthoff E, Agaimy A, Schneider-Stock R.
Spectrum of KIT/PDGFRA/BRAF mutations and Phosphatidylinositol-3-Kinase pathway gene
alterations in gastrointestinal stromal tumors (GIST).

Cancer Lett. 2011 Dec 15;312(1):43-54. doi: 10.1016/j.canlet.2011.07.029.
PubMed PMID: 21906875

Falchook GS, Trent JC, Heinrich MC, Beadling C, Patterson J, Bastida CC, Blackman SC, Kurzrock R. BRAF mutant gastrointestinal stromal tumor: first report of regression with BRAF inhibitor dabrafenib (GSK2118436) and whole exomic sequencing for analysis of acquired resistance.
Oncotarget. 2013 Feb;4(2):310-5.
PubMed PMID: 23470635; PubMed Central PMCID: PMC3712576.

Hostein I, Faur N, Primois C, Boury F, Denard J, Emile JF, Bringuier PP, Scoazec JY, Coindre JM.
BRAF mutation status in gastrointestinal stromal tumors.
Am J Clin Pathol. 2010 Jan;133(1):141-8.
PubMed PMID: 20023270.

Martinho O, Gouveia A, Viana-Pereira M, Silva P, Pimenta A, Reis RM, Lopes JM.
Low frequency of MAP kinase pathway alterations in KIT and PDGFRA wild-type GISTs.
Histopathology. 2009 Jul;55(1):53-62.
PubMed PMID: 19614767.



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