title: Transcriptome sequencing identifies ETV6-NTRK3 as a gene fusion involved in GIST.
abstract: Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. The vast majority of GISTs are driven by oncogenic activation of KIT, PDGFRA or, less commonly, BRAF. Loss of succinate dehydrogenase complex activity has been identified in subsets of KIT/PDGFRA/BRAF-mutation negative tumours, yet a significant fraction of GISTs are devoid of any of such alterations. To address the pathobiology of these 'quadruple-negative' GISTs, we sought to explore the possible involvement of fusion genes. To this end we performed transcriptome sequencing on five KIT/PDGFRA/BRAF-mutation negative, SDH-proficient tumours. Intriguingly, the analysis unveiled the presence of an ETV6-NTRK3 gene fusion. The screening by FISH of 26 additional cases, including KIT/PDGFRA-mutated GISTs, failed to detect other ETV6 rearrangements beside the index case. This was a 'quadruple-negative' GIST located in the rectum, an uncommon primary site for GIST development (∼4% of all GISTs). The fusion transcript identified encompasses exon 4 of ETV6 and exon 14 of NTRK3 and therefore differs from the canonical ETV6-NTRK3 chimera of infantile fibrosarcomas. However, it retains the ability to induce IRS1 phosphorylation, activate the IGF1R downstream signalling pathway and to be targeted by IGF1R and ALK inhibitors. Thus, the ETV6-NTRK3 fusion might identify a subset of GISTs with peculiar clinicopathological characteristics which could be eligible for such therapies. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Experimental Oncology 1, CRO Aviano National Cancer Institute, Aviano, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Brenca
authors.affiliation: Department of Pathology, Treviso General Hospital, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Rossi
authors.affiliation: Experimental Oncology 1, CRO Aviano National Cancer Institute, Aviano, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Polano
authors.affiliation: Experimental Oncology 1, CRO Aviano National Cancer Institute, Aviano, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Gasparotto
authors.affiliation: Department of Pathology, Treviso General Hospital, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Zanatta
authors.affiliation: Experimental Oncology 1, CRO Aviano National Cancer Institute, Aviano, Italy.
authors.forename: Dominga
authors.initials: D
authors.lastname: Racanelli
authors.affiliation: Department of Pathology, Treviso General Hospital, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Valori
authors.affiliation: Department of Oncology, Treviso General Hospital, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Lamon
authors.affiliation: Department of Pathology, Treviso General Hospital, Italy.
authors.forename: Angelo Paolo
authors.initials: AP
authors.lastname: Dei Tos
authors.affiliation: Experimental Oncology 1, CRO Aviano National Cancer Institute, Aviano, Italy.
authors.forename: Roberta
authors.identifier: http://orcid.org/0000-0002-6642-5592
authors.initials: R
authors.lastname: Maestro
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D005091:Exons / Q000235:genetics; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics* / Q000473:pathology*; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics*; D050939:Gene Fusion / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D020812:Receptor, trkC / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D050783:Proto-Oncogene Proteins c-ets; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020812:Receptor, trkC; D012097:Repressor Proteins; D000097764:ETS Translocation Variant 6 Protein
keywords: ETV6-NTRK3 chimera; GIST; fusion genes; transcriptome sequencing