NTRK1 fusion in glioblastoma multiforme

PLoS One. 2014 Mar 19;9(3):e91940. doi: 10.1371/journal.pone.0091940. eCollection 2014.

Abstract

Glioblastoma multiforme (GBM) is the most aggressive form of brain tumor, yet with no targeted therapy with substantial survival benefit. Recent studies on solid tumors showed that fusion genes often play driver roles and are promising targets for pharmaceutical intervention. To survey potential fusion genes in GBMs, we analysed RNA-Seq data from 162 GBM patients available through The Cancer Genome Atlas (TCGA), and found that 3' exons of neurotrophic tyrosine kinase receptor type 1 (NTRK1, encoding TrkA) are fused to 5' exons of the genes that are highly expressed in neuronal tissues, neurofascin (NFASC) and brevican (BCAN). The fusions preserved both the transmembrane and kinase domains of NTRK1 in frame. NTRK1 is a mediator of the pro-survival signaling of nerve growth factor (NGF) and is a known oncogene, found commonly altered in human cancer. While GBMs largely lacked NTRK1 expression, the fusion-positive GBMs expressed fusion transcripts in high abundance, and showed elevated NTRK1-pathway activity. Lentiviral transduction of the NFASC-NTRK1 fusion gene in NIH 3T3 cells increased proliferation in vitro, colony formation in soft agar, and tumor formation in mice, suggesting the possibility that the fusion contributed to the initiation or maintenance of the fusion-positive GBMs, and therefore may be a rational drug target.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Brain Neoplasms / metabolism*
  • Brevican / chemistry
  • Brevican / genetics
  • Brevican / metabolism*
  • Carcinogenesis / pathology
  • Cell Adhesion Molecules / chemistry
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism*
  • Glioblastoma / metabolism*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Molecular Sequence Data
  • NIH 3T3 Cells
  • Nerve Growth Factors / chemistry
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / metabolism
  • Oncogene Proteins, Fusion / chemistry
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism*
  • Receptor, trkA / chemistry
  • Receptor, trkA / genetics
  • Receptor, trkA / metabolism*

Substances

  • BCAN protein, human
  • Brevican
  • Cell Adhesion Molecules
  • NFASC protein, human
  • Nerve Growth Factors
  • Oncogene Proteins, Fusion
  • BCAN-NTRK1 fusion protein, human
  • NFASC-NTRK1 fusion protein, human
  • Receptor, trkA

Grant support

This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI09C1552), and by a grant from Samsung Medical Center (GFO1130011). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.