Novel SEC61G-EGFR fusion gene in pediatric ependymomas discovered by clonal expansion of stem cells in absence of exogenous mitogens

Massimiliano Mirabella, Maurizio Martini, Tiziana Servidei, Daniela Meco, Matteo Lucchini, Roberta Morosetti, Massimo Caldarelli, Marco Tartaglia, Riccardo Riccardi, Valentina Muto, Alessandro Bruselles, Andrea Ciolfi, Nadia Trivieri, Anna Lasorella

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

The basis for molecular and cellular heterogeneity in ependymomas of the central nervous system is not understood. This study suggests a basis for this phenomenon in the selection for mitogen-independent (MI) stem-like cells with impaired proliferation but increased intracranial tumorigenicity. MI ependymoma cell lines created by selection for EGF/FGF2-independent proliferation exhibited constitutive activation of EGFR, AKT, and STAT3 and sensitization to the antiproliferative effects of EGFR tyrosine kinase inhibitors (TKI). One highly tumorigenic MI line harbored membrane-bound, constitutively active, truncated EGFR. Two EGFR mutants (ΔN566 and ΔN599) were identified as products of intrachromosomal rearrangements fusing the 30 coding portion of the EGFR gene to the 50-UTR of the SEC61G, yielding products lacking the entire extracellular ligand-binding domain of the receptor while retaining the transmembrane and tyrosine kinase domains. EGFR TKI efficiently targeted ΔN566/ΔN599-mutant-mediated signaling and prolonged the survival of mice bearing intracranial xenografts of MI cells harboring these mutations. RT-PCR sequencing of 16 childhood ependymoma samples identified SEC61G-EGFR chimeric mRNAs in one infratentorial ependymoma WHO III, arguing that this fusion occurs in a small proportion of these tumors. Our findings demonstrate how in vitro culture selections applied to genetically heterogeneous tumors can help identify focal mutations that are potentially pharmaceutically actionable in rare cancers.
Original languageEnglish
Pages (from-to)5860-5872
Number of pages13
JournalCancer Research
Volume77
DOIs
Publication statusPublished - 2017

Keywords

  • Amino Acid Sequence
  • Animals
  • Cancer Research
  • Cell Line, Tumor
  • Cell Proliferation
  • Child
  • Clone Cells
  • Ependymoma
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Mice, Nude
  • Mitogens
  • Mutation
  • Oncology
  • Protein Kinase Inhibitors
  • Receptor, Epidermal Growth Factor
  • Recombinant Fusion Proteins
  • Reverse Transcriptase Polymerase Chain Reaction
  • SEC Translocation Channels
  • Stem Cells
  • Transplantation, Heterologous

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