Research Papers: Pathology:
Concomitant KIT/BRAF and PDGFRA/BRAF mutations are rare events in gastrointestinal stromal tumors
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Sabrina Rossi1, Marta Sbaraglia1, Marta Campo Dell’Orto1, Daniela Gasparotto2, Matilde Cacciatore1, Elena Boscato1, Valentina Carraro1, Luisa Toffolatti1, Giovanna Gallina1, Monia Niero1, Emanuela Pilozzi3, Alessandra Mandolesi4, Fausto Sessa5, Aurelio Sonzogni6, Cristina Mancini7, Guido Mazzoleni8, Salvatore Romeo1, Roberta Maestro2,* and Angelo P. Dei Tos1,*
1 Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy
2 Department of Experimental Oncology, CRO, Aviano, Italy
3 Department of Clinical and Molecular Medicine, University of Rome “La Sapienza”, Rome, Italy
4 Department of Pathology, University of Marche, Ancona School of Medicine, Ancona, Italy
5 Department of Pathology, Macchi Fondation, Varese, Italy
6 Department of Pathology, General Hospital, Bergamo, Italy
7 Department of Pathology, Azienda Ospedaliera-Universitaria, Parma, Italy
8 Department of Pathology, General Hospital, Bolzano, Italy
* These authors have contributed equally to the work
Angelo P. Dei Tos, email:
Keywords: GIST, BRAF-mutated GIST, KIT/BRAF concomitant mutations, Imatinib resistance, BRAF VE1 antibody, Pathology Section
Received: December 30, 2015 Accepted: April 04, 2016 Published: April 16, 2016
AIM: 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.
CONCLUSION: 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.
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