Transcriptome sequencing identifies ETV6–NTRK3 as a gene fusion involved in GIST
Top Cited Papers
Open Access
- 26 November 2015
- journal article
- research article
- Published by Wiley in The Journal of Pathology
- Vol. 238 (4), 543-549
- https://doi.org/10.1002/path.4677
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.Keywords
Funding Information
- Associazione Italiana Ricerca sul Cancro (AIRC)
- Italian Ministry of Health and a Centro di Riferimento Oncologico di Aviano
- Fondazione Italiana Ricerca sul Cancro (FIRC)
This publication has 24 references indexed in Scilit:
- Expression of the Receptor for Type I Insulin-like Growth Factor (IGF1R) in Gastrointestinal Stromal TumorsThe American Journal of Surgical Pathology, 2013
- Targeting the Insulin Growth Factor Receptor 1Hematology/Oncology Clinics of North America, 2012
- Nuclear IRS‐1 and cancerJournal of Cellular Physiology, 2011
- ChimeraScan: a tool for identifying chimeric transcription in sequencing dataBioinformatics, 2011
- Chronic eosinophilic leukaemia with ETV6-NTRK3 fusion transcript in an elderly patient affected with pancreatic carcinomaEuropean Journal of Haematology, 2011
- Mammary Analogue Secretory Carcinoma of Salivary Glands, Containing the ETV6-NTRK3 Fusion Gene: A Hitherto Undescribed Salivary Gland Tumor EntityThe American Journal of Surgical Pathology, 2010
- Multiple Primary Sporadic Gastrointestinal Stromal Tumors in the Adult: An Underestimated EntityClinical Cancer Research, 2008
- A Highly Conserved NTRK3 C-terminal Sequence in the ETV6-NTRK3 Oncoprotein Binds the Phosphotyrosine Binding Domain of Insulin Receptor Substrate-1Published by Elsevier BV ,2004
- ETV6-NTRK3 transformation requires insulin-like growth factor 1 receptor signaling and is associated with constitutive IRS-1 tyrosine phosphorylationOncogene, 2002
- A novel ETV6-NTRK3 gene fusion in congenital fibrosarcomaNature Genetics, 1998