Abstract
Original language | English |
---|---|
Pages (from-to) | 5860-5872 |
Number of pages | 13 |
Journal | Cancer Research |
Volume | 77 |
Issue number | 21 |
DOIs | |
Publication status | Published - 2017 |
Keywords
- 6 [4 (4 ethyl 1 piperazinylmethyl)phenyl] 4 (alpha methylbenzylamino) 7h pyrrolo[2,3 d]pyrimidine
- CD133 antigen
- epidermal growth factor receptor
- gefitinib
- messenger RNA
- nestin
- oligodendrocyte transcription factor 2
- protein kinase B
- STAT3 protein
- transcription factor Sox2
- hybrid protein
- mitogenic agent
- protein kinase inhibitor
- SEC61G protein, human
- translocon
- animal experiment
- animal model
- animal tissue
- antiproliferative activity
- Article
- carcinogenesis
- cell proliferation
- child
- chromosome rearrangement
- clinical article
- controlled study
- ependymoma
- ependymoma cell line
- fusion gene
- gene mutation
- human
- human cell
- human tissue
- male
- mouse
- nonhuman
- priority journal
- reverse transcription polymerase chain reaction
- SEC61G EGFR fusion gene
- stem cell
- tumor engraftment
- tumor xenograft
- amino acid sequence
- animal
- antagonists and inhibitors
- cell clone
- drug effects
- gene expression regulation
- genetics
- Kaplan Meier method
- metabolism
- mutation
- nude mouse
- pathology
- tumor cell line
- xenograft
- Amino Acid Sequence
- Animals
- Cell Line, Tumor
- Cell Proliferation
- Child
- Clone Cells
- Ependymoma
- Gene Expression Regulation, Neoplastic
- Humans
- Kaplan-Meier Estimate
- Male
- Mice, Nude
- Mitogens
- Mutation
- 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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Novel SEC61G-EGFR fusion gene in pediatric ependymomas discovered by clonal expansion of stem cells in absence of exogenous mitogens. / Servidei, T.; Meco, D.; Muto, V.; Bruselles, A.; Ciolfi, A.; Trivieri, N.; Lucchini, M.; Morosetti, R.; Mirabella, M.; Martini, M.; Caldarelli, M.; Lasorella, A.; Tartaglia, M.; Riccardi, R.
In: Cancer Research, Vol. 77, No. 21, 2017, p. 5860-5872.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Novel SEC61G-EGFR fusion gene in pediatric ependymomas discovered by clonal expansion of stem cells in absence of exogenous mitogens
AU - Servidei, T.
AU - Meco, D.
AU - Muto, V.
AU - Bruselles, A.
AU - Ciolfi, A.
AU - Trivieri, N.
AU - Lucchini, M.
AU - Morosetti, R.
AU - Mirabella, M.
AU - Martini, M.
AU - Caldarelli, M.
AU - Lasorella, A.
AU - Tartaglia, M.
AU - Riccardi, R.
N1 - Export Date: 6 April 2018 CODEN: CNREA Correspondence Address: Servidei, T.; UOC Oncologia Pediatrica, Fondazione Policlinico Universitario 'A Gemelli'Italy; email: tiziana.servidei@guest.policlinicogemelli.it Chemicals/CAS: 6 [4 (4 ethyl 1 piperazinylmethyl)phenyl] 4 (alpha methylbenzylamino) 7h pyrrolo[2,3 d]pyrimidine, 497839-62-0; epidermal growth factor receptor, 79079-06-4; gefitinib, 184475-35-2, 184475-55-6, 184475-56-7; nestin, 146315-66-4; protein kinase B, 148640-14-6; Mitogens; Protein Kinase Inhibitors; Receptor, Epidermal Growth Factor; Recombinant Fusion Proteins; SEC Translocation Channels; SEC61G protein, human Tradenames: aee 788, Novartis Manufacturers: Astra Zeneca; Novartis References: Kilday, J.P., Rahman, R., Dyer, S., Ridley, L., Lowe, J., Coyle, B., Pediatric ependymoma: Biological perspectives (2009) Mol Cancer Res, 7, pp. 765-786; Korshunov, A., Witt, H., Hielscher, T., Benner, A., Remke, M., Ryzhova, M., Molecular staging of intracranial ependymoma in children and adults (2010) J Clin Oncol, 28, pp. 3182-3190; 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PY - 2017
Y1 - 2017
N2 - 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. © 2017 American Association for Cancer Research.
AB - 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. © 2017 American Association for Cancer Research.
KW - 6 [4 (4 ethyl 1 piperazinylmethyl)phenyl] 4 (alpha methylbenzylamino) 7h pyrrolo[2,3 d]pyrimidine
KW - CD133 antigen
KW - epidermal growth factor receptor
KW - gefitinib
KW - messenger RNA
KW - nestin
KW - oligodendrocyte transcription factor 2
KW - protein kinase B
KW - STAT3 protein
KW - transcription factor Sox2
KW - hybrid protein
KW - mitogenic agent
KW - protein kinase inhibitor
KW - SEC61G protein, human
KW - translocon
KW - animal experiment
KW - animal model
KW - animal tissue
KW - antiproliferative activity
KW - Article
KW - carcinogenesis
KW - cell proliferation
KW - child
KW - chromosome rearrangement
KW - clinical article
KW - controlled study
KW - ependymoma
KW - ependymoma cell line
KW - fusion gene
KW - gene mutation
KW - human
KW - human cell
KW - human tissue
KW - male
KW - mouse
KW - nonhuman
KW - priority journal
KW - reverse transcription polymerase chain reaction
KW - SEC61G EGFR fusion gene
KW - stem cell
KW - tumor engraftment
KW - tumor xenograft
KW - amino acid sequence
KW - animal
KW - antagonists and inhibitors
KW - cell clone
KW - drug effects
KW - gene expression regulation
KW - genetics
KW - Kaplan Meier method
KW - metabolism
KW - mutation
KW - nude mouse
KW - pathology
KW - tumor cell line
KW - xenograft
KW - Amino Acid Sequence
KW - Animals
KW - Cell Line, Tumor
KW - Cell Proliferation
KW - Child
KW - Clone Cells
KW - Ependymoma
KW - Gene Expression Regulation, Neoplastic
KW - Humans
KW - Kaplan-Meier Estimate
KW - Male
KW - Mice, Nude
KW - Mitogens
KW - Mutation
KW - Protein Kinase Inhibitors
KW - Receptor, Epidermal Growth Factor
KW - Recombinant Fusion Proteins
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - SEC Translocation Channels
KW - Stem Cells
KW - Transplantation, Heterologous
U2 - 10.1158/0008-5472.CAN-17-0790
DO - 10.1158/0008-5472.CAN-17-0790
M3 - Article
VL - 77
SP - 5860
EP - 5872
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 21
ER -