Concomitant KIT/BRAF and PDGFRA/BRAF mutations are rare events in gastrointestinal stromal tumors.
OBJECTIVE
The BRAF mutation is a rare pathogenetic alternative to KIT/PDGFRA mutation in GIST and causes Imatinib resistance. A recent description of KIT and BRAF mutations co-occurring in an untreated GIST has challenged the concept of their being mutually exclusive and may account for ab initio resistance to Imatinib, even in the presence of Imatinib-sensitive KIT mutations. BRAF sequencing is generally limited to KIT/PDGFRA wild-type cases. Hence, the frequency of concomitant mutations may be underestimated.


METHODS
We screened for KIT (exon 9, 11 ,13 ,17), PDGFRA (exon 12,14, 18) and BRAF (exon 15) mutations a series of 407 GIST. Additionally, we evaluated the BRAF V600E mutation-specific antibody, VE1, as a surrogate for V600E mutation, on a series of 313 GIST (24 on whole sections, 288 cases on tissue array), including 6 cases molecularly ascertained to carry the BRAF V600E mutation.


RESULTS
No concomitant KIT/BRAF or PDGFRA/BRAF mutations were detected. BRAF mutation was detected only in one case, wild-type for KIT/PDGFRA. All the 6 BRAF-mutant cases stained positive with the VE1 antibody. A weak VE1 expression was observed in 14/287 (4.9%) BRAF wild-type cases, as observed also in 2/6 BRAF-mutant cases. Overall in our series, sensitivity and specificity of the VE1 antobody were 100% and 95.1%, respectively.


CONCLUSIONS
The concomitance of BRAF mutation with either KIT or PDGFRA mutation is rare in GIST. In these tumors, moderate/strong VE1 immunoreactivity is a valuable surrogate for molecular analysis. Instead, genotyping is warranted in the presence of weak VE1 staining.
Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy.
Sabrina
S
Rossi
Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy.
Marta
M
Sbaraglia
Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy.
Marta Campo
MC
Dell'Orto
Department of Experimental Oncology, CRO, Aviano, Italy.
Daniela
D
Gasparotto
Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy.
Matilde
M
Cacciatore
Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy.
Elena
E
Boscato
Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy.
Valentina
V
Carraro
Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy.
Luisa
L
Toffolatti
Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy.
Giovanna
G
Gallina
Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy.
Monia
M
Niero
Department of Clinical and Molecular Medicine, University of Rome "La Sapienza", Rome, Italy.
Emanuela
E
Pilozzi
Department of Pathology, University of Marche, Ancona School of Medicine, Ancona, Italy.
Alessandra
A
Mandolesi
Department of Pathology, Macchi Fondation, Varese, Italy.
Fausto
F
Sessa
Department of Pathology, General Hospital, Bergamo, Italy.
Aurelio
A
Sonzogni
Department of Pathology, Azienda Ospedaliera-Universitaria, Parma, Italy.
Cristina
C
Mancini
Department of Pathology, General Hospital, Bolzano, Italy.
Guido
G
Mazzoleni
Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy.
Salvatore
S
Romeo
Department of Experimental Oncology, CRO, Aviano, Italy.
Roberta
R
Maestro
Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy.
Angelo P
AP
Dei Tos
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D004252:DNA Mutational Analysis / Q000379:methods; D019008:Drug Resistance, Neoplasm; D005091:Exons; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics* / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D005838:Genotype; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology / Q000627:therapeutic use; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000276:immunology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D017422:Sequence Analysis, DNA; D046888:Tissue Array Analysis
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
BRAF VE1 antibody; BRAF-mutated GIST; GIST; Imatinib resistance; KIT/BRAF concomitant mutations; Pathology Section