Concomitant KIT/BRAF and PDGFRA/BRAF mutations are rare events in gastrointestinal stromal tumors

// Sabrina Rossi 1 , Marta Sbaraglia 1 , Marta Campo Dell’Orto 1 , Daniela Gasparotto 2 , Matilde Cacciatore 1 , Elena Boscato 1 , Valentina Carraro 1 , Luisa Toffolatti 1 , Giovanna Gallina 1 , Monia Niero 1 , Emanuela Pilozzi 3 , Alessandra Mandolesi 4 , Fausto Sessa 5 , Aurelio Sonzogni 6 , Cristina Mancini 7 , Guido Mazzoleni 8 , Salvatore Romeo 1 , Roberta Maestro 2,* and Angelo P. Dei Tos 1,* 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 Correspondence to: 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 Abstract 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.