American Association for Cancer Research
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00085472can170790-sup-179581_2_supp_4219651_5552gn.xlsx (30.94 kB)

Supplementary Table S1 from Novel SEC61GEGFR Fusion Gene in Pediatric Ependymomas Discovered by Clonal Expansion of Stem Cells in Absence of Exogenous Mitogens

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posted on 2023-03-31, 01:40 authored by Tiziana Servidei, Daniela Meco, Valentina Muto, Alessandro Bruselles, Andrea Ciolfi, Nadia Trivieri, Matteo Lucchini, Roberta Morosetti, Massimiliano Mirabella, Maurizio Martini, Massimo Caldarelli, Anna Lasorella, Marco Tartaglia, Riccardo Riccardi

Fusion transcripts identified by ChimeraScan in EPP-MI line

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Associazione Italiana per la Ricerca sul Cancro

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ARTICLE 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 3′ coding portion of the EGFR gene to the 5′-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. Cancer Res; 77(21); 5860–72. ©2017 AACR.

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