Recurrent SPECC1L–NTRK fusions in pediatric sarcoma and brain tumors

  1. Paul G. Ekert1,3,5,6
  1. 1Children's Cancer Institute, University of New South Wales, Randwick, 2031, Australia;
  2. 2Children's Cancer Centre, Royal Children's Hospital, Parkville, 3052, Australia;
  3. 3Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, 3052, Australia;
  4. 4Department of Pediatrics, University of Melbourne, Parkville, 3052, Australia;
  5. 5School of Women's and Children's Health, UNSW Medicine, UNSW Sydney, Randwick, 2031, Australia;
  6. 6Peter MacCallum Cancer Centre, Melbourne, 3000, Australia;
  7. 7Kids Cancer Centre, Sydney Children's Hospital, Randwick, 2031, Australia;
  8. 8Department of Anatomical Pathology, Prince of Wales Hospital, Randwick, 2031, Australia;
  9. 9Sir Peter MacCallum Department of Oncology, University of Melbourne, 3000, Australia;
  10. 10Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, 3000, Australia
  1. Corresponding author: PEkert{at}ccia.org.au

Abstract

The identification of rearrangements driving expression of neurotrophic receptor tyrosine kinase (NTRK) family kinases in tumors has become critically important because of the availability of effective, specific inhibitor drugs. Whole-genome sequencing (WGS) combined with RNA sequencing (RNA-seq) can identify novel and recurrent expressed fusions. Here we describe three SPECC1L–NTRK fusions identified in two pediatric central nervous system cancers and an extracranial solid tumor using WGS and RNA-seq. These fusions arose either through a simple balanced rearrangement or in the context of a complex chromoplexy event. We cloned the SPECC1L–NTRK2 fusion directly from a patient sample and showed that enforced expression of this fusion is sufficient to promote cytokine-independent survival and proliferation. Cells transformed by SPECC1L–NTRK2 expression are sensitive to a TRK inhibitor drug. We report here that SPECC1L–NTRK fusions can arise in a range of pediatric cancers. Although WGS and RNA-seq are not required to detect NTRK fusions, these techniques may be of benefit when NTRK fusions are not suspected on clinical grounds or not identified by other methods.

Footnotes

  • [Supplemental material is available for this article.]

  • Received July 22, 2020.
  • Accepted October 22, 2020.

This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License, which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.

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  1. Cold Spring Harb Mol Case Stud 6: a005710 © 2020 Khuong-Quang et al.; Published by Cold Spring Harbor Laboratory Press
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