Clinicopathological and molecular features of a large cohort of gastrointestinal stromal tumors (GISTs) and review of the literature: BRAF mutations in KIT/PDGFRA wild-type GISTs are rare events.
In KIT/PDGFRA wild-type gastrointestinal stromal tumors (wt-GISTs), BRAF mutations are regarded as alternative pathogenic events driving tumorigenesis. In our study, we aimed at analyzing a large cohort (n=444) of GISTs for BRAF mutations using molecular and immunohistochemical methods. More than 3000 GIST samples from caucasian patients were available in our GIST and Sarcoma Registry NRW. Of these, we selected 172 wt-GISTs to evaluate the frequency of BRAF mutations. Furthermore, 272 GISTs with a representative KIT and PDGFRA mutational status were selected. BRAF mutational status was evaluated by high-resolution melting analysis, Sanger sequencing, and VE1 immunohistochemistry. A BRAF mutation (p.V600E) was found in 7 cases (3.9%) of the wt-GIST cohort. In 2 cases, multiple synchronous tumors harbored the same somatic BRAF mutation. VE1 immunohistochemical staining had a sensitivity of 81.8% and a specificity of 97.5% to detect BRAF p.V600E mutations. Analyzing our cases and the cases reported in the literature (n=37), the percentage of intermediate and high-risk BRAF-mutated wt-GISTs (17/31; 54.8%) was comparable to that recorded for large GIST cohorts irrespective of the mutational status. BRAF mutations are rare events in wt-GISTs, and VE1 immunohistochemistry appears to be a valuable pre-screening tool for the detection of BRAF p.V600E mutations. BRAF mutations in GISTs do not seem to have a prognostic value per se. However, as BRAF inhibition represents a therapeutic option to control disease, we suggest the assessment of the BRAF mutational status, especially in the setting of advanced GIST disease.
Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48156 Münster, Germany. Electronic address: Sebastian.Huss@ukmuenster.de.
Sebastian
S
Huss
Pathology of the University Medical Center Schleswig-Holstein, Campus Luebeck and the Research Center Borstel, Leibniz Center for Medicine and Biosciences, Ratzeburger Allee 160, 23538 Luebeck, Germany. Electronic address: Helen.Pasternack@uksh.de.
Helen
H
Pasternack
Institute of Pathology, University Hospital Cologne, Kerpener Strasse 62, 50937 Cologne, Germany. Electronic address: michaela.ihle@uk-koeln.de.
Michaela Angelika
MA
Ihle
Institute of Pathology, University Hospital Cologne, Kerpener Strasse 62, 50937 Cologne, Germany. Electronic address: sabine.merkelbach-bruse@uk-koeln.de.
Sabine
S
Merkelbach-Bruse
Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48156 Münster, Germany. Electronic address: Birthe.heitkotter@ukmuenster.de.
Birthe
B
Heitkötter
Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48156 Münster, Germany. Electronic address: Wolfgang.Hartmann@ukmuenster.de.
Wolfgang
W
Hartmann
Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48156 Münster, Germany. Electronic address: Marcel.Trautmann@ukmuenster.de.
Marcel
M
Trautmann
Institute of Pathology, University Hospital Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany. Electronic address: Heidrun.Gevensleben@ukb.uni-bonn.de.
Heidrun
H
Gevensleben
Institute of Pathology, University Hospital Cologne, Kerpener Strasse 62, 50937 Cologne, Germany. Electronic address: reinhard.buettner@uk-koeln.de.
Reinhard
R
Büttner
Institute of Pathology, University Hospital Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, Germany. Electronic address: hans-ulrich.schildhaus@med.uni-goettingen.de.
Hans-Ulrich
HU
Schildhaus
Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48156 Münster, Germany. Electronic address: Eva.Wardelmann@ukmuenster.de.
Eva
E
Wardelmann
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D008940:Mitotic Index; D009154:Mutation; D010641:Phenotype; D011237:Predictive Value of Tests; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D012042:Registries; D015203:Reproducibility of Results; D047368:Tumor Burden
D014408:Biomarkers, Tumor; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
BRAF; GIST; Prognosis; VE1; Wild type