Transcriptome sequencing identifies ETV6-NTRK3 as a gene fusion involved in GIST

Monica Brenca, Sabrina Rossi, Maurizio Polano, Daniela Gasparotto, Lucia Zanatta, Dominga Racanelli, Laura Valori, Stefano Lamon, Angelo Paolo Dei Tos, Roberta Maestro

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)543-549
Number of pages7
JournalJournal of Pathology
Issue number4
Publication statusPublished - Mar 1 2016


  • ETV6-NTRK3 chimera
  • fusion genes
  • GIST
  • transcriptome sequencing

ASJC Scopus subject areas

  • Pathology and Forensic Medicine


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