Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma

David T W Jones, Barbara Hutter, Natalie Jäger, Andrey Korshunov, Marcel Kool, Hans Jörg Warnatz, Thomas Zichner, Sally R. Lambert, Marina Ryzhova, Dong Anh Khuong Quang, Adam M. Fontebasso, Adrian M. Stütz, Sonja Hutter, Marc Zuckermann, Dominik Sturm, Jan Gronych, Bärbel Lasitschka, Sabine Schmidt, Huriye Şeker-Cin, Hendrik Witt & 55 others Marc Sultan, Meryem Ralser, Paul A. Northcott, Volker Hovestadt, Sebastian Bender, Elke Pfaff, Sebastian Stark, Damien Faury, Jeremy Schwartzentruber, Jacek Majewski, Ursula D. Weber, Marc Zapatka, Benjamin Raeder, Matthias Schlesner, Catherine L. Worth, Cynthia C. Bartholomae, Christof Von Kalle, Charles D. Imbusch, Sylwester Radomski, Chris Lawerenz, Peter Van Sluis, Jan Koster, Richard Volckmann, Rogier Versteeg, Hans Lehrach, Camelia Monoranu, Beate Winkler, Andreas Unterberg, Christel Herold Mende, Till Milde, Andreas E. Kulozik, Martin Ebinger, Martin U. Schuhmann, Yoon Jae Cho, Scott L. Pomeroy, Andreas Von Deimling, Olaf Witt, Michael D. Taylor, Stephan Wolf, Matthias A. Karajannis, Charles G Eberhart, Wolfram Scheurlen, Martin Hasselblatt, Keith L. Ligon, Mark W. Kieran, Jan O. Korbel, Marie Laure Yaspo, Benedikt Brors, Jörg Felsberg, Guido Reifenberger, V. Peter Collins, Nada Jabado, Roland Eils, Peter Lichter, Stefan M. Pfister

Research output: Contribution to journalArticle

Abstract

Pilocytic astrocytoma, the most common childhood brain tumor, is typically associated with mitogen-activated protein kinase (MAPK) pathway alterations. Surgically inaccessible midline tumors are therapeutically challenging, showing sustained tendency for progression and often becoming a chronic disease with substantial morbidities. Here we describe whole-genome sequencing of 96 pilocytic astrocytomas, with matched RNA sequencing (n = 73), conducted by the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. We identified recurrent activating mutations in FGFR1 and PTPN11 and new NTRK2 fusion genes in non-cerebellar tumors. New BRAF-activating changes were also observed. MAPK pathway alterations affected all tumors analyzed, with no other significant mutations identified, indicating that pilocytic astrocytoma is predominantly a single-pathway disease. Notably, we identified the same FGFR1 mutations in a subset of H3F3A-mutated pediatric glioblastoma with additional alterations in the NF1 gene. Our findings thus identify new potential therapeutic targets in distinct subsets of pilocytic astrocytoma and childhood glioblastoma.

Original languageEnglish (US)
Pages (from-to)927-932
Number of pages6
JournalNature Genetics
Volume45
Issue number8
DOIs
StatePublished - Aug 2013

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Astrocytoma
Neoplasms
Glioblastoma
Mitogen-Activated Protein Kinases
Mutation
Genome
RNA Sequence Analysis
Gene Fusion
Brain Neoplasms
Chronic Disease
Pediatrics
Morbidity
Genes

ASJC Scopus subject areas

  • Genetics

Cite this

Jones, D. T. W., Hutter, B., Jäger, N., Korshunov, A., Kool, M., Warnatz, H. J., ... Pfister, S. M. (2013). Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nature Genetics, 45(8), 927-932. https://doi.org/10.1038/ng.2682

Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. / Jones, David T W; Hutter, Barbara; Jäger, Natalie; Korshunov, Andrey; Kool, Marcel; Warnatz, Hans Jörg; Zichner, Thomas; Lambert, Sally R.; Ryzhova, Marina; Quang, Dong Anh Khuong; Fontebasso, Adam M.; Stütz, Adrian M.; Hutter, Sonja; Zuckermann, Marc; Sturm, Dominik; Gronych, Jan; Lasitschka, Bärbel; Schmidt, Sabine; Şeker-Cin, Huriye; Witt, Hendrik; Sultan, Marc; Ralser, Meryem; Northcott, Paul A.; Hovestadt, Volker; Bender, Sebastian; Pfaff, Elke; Stark, Sebastian; Faury, Damien; Schwartzentruber, Jeremy; Majewski, Jacek; Weber, Ursula D.; Zapatka, Marc; Raeder, Benjamin; Schlesner, Matthias; Worth, Catherine L.; Bartholomae, Cynthia C.; Von Kalle, Christof; Imbusch, Charles D.; Radomski, Sylwester; Lawerenz, Chris; Van Sluis, Peter; Koster, Jan; Volckmann, Richard; Versteeg, Rogier; Lehrach, Hans; Monoranu, Camelia; Winkler, Beate; Unterberg, Andreas; Mende, Christel Herold; Milde, Till; Kulozik, Andreas E.; Ebinger, Martin; Schuhmann, Martin U.; Cho, Yoon Jae; Pomeroy, Scott L.; Von Deimling, Andreas; Witt, Olaf; Taylor, Michael D.; Wolf, Stephan; Karajannis, Matthias A.; Eberhart, Charles G; Scheurlen, Wolfram; Hasselblatt, Martin; Ligon, Keith L.; Kieran, Mark W.; Korbel, Jan O.; Yaspo, Marie Laure; Brors, Benedikt; Felsberg, Jörg; Reifenberger, Guido; Collins, V. Peter; Jabado, Nada; Eils, Roland; Lichter, Peter; Pfister, Stefan M.

In: Nature Genetics, Vol. 45, No. 8, 08.2013, p. 927-932.

Research output: Contribution to journalArticle

Jones, DTW, Hutter, B, Jäger, N, Korshunov, A, Kool, M, Warnatz, HJ, Zichner, T, Lambert, SR, Ryzhova, M, Quang, DAK, Fontebasso, AM, Stütz, AM, Hutter, S, Zuckermann, M, Sturm, D, Gronych, J, Lasitschka, B, Schmidt, S, Şeker-Cin, H, Witt, H, Sultan, M, Ralser, M, Northcott, PA, Hovestadt, V, Bender, S, Pfaff, E, Stark, S, Faury, D, Schwartzentruber, J, Majewski, J, Weber, UD, Zapatka, M, Raeder, B, Schlesner, M, Worth, CL, Bartholomae, CC, Von Kalle, C, Imbusch, CD, Radomski, S, Lawerenz, C, Van Sluis, P, Koster, J, Volckmann, R, Versteeg, R, Lehrach, H, Monoranu, C, Winkler, B, Unterberg, A, Mende, CH, Milde, T, Kulozik, AE, Ebinger, M, Schuhmann, MU, Cho, YJ, Pomeroy, SL, Von Deimling, A, Witt, O, Taylor, MD, Wolf, S, Karajannis, MA, Eberhart, CG, Scheurlen, W, Hasselblatt, M, Ligon, KL, Kieran, MW, Korbel, JO, Yaspo, ML, Brors, B, Felsberg, J, Reifenberger, G, Collins, VP, Jabado, N, Eils, R, Lichter, P & Pfister, SM 2013, 'Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma', Nature Genetics, vol. 45, no. 8, pp. 927-932. https://doi.org/10.1038/ng.2682
Jones DTW, Hutter B, Jäger N, Korshunov A, Kool M, Warnatz HJ et al. Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nature Genetics. 2013 Aug;45(8):927-932. https://doi.org/10.1038/ng.2682
Jones, David T W ; Hutter, Barbara ; Jäger, Natalie ; Korshunov, Andrey ; Kool, Marcel ; Warnatz, Hans Jörg ; Zichner, Thomas ; Lambert, Sally R. ; Ryzhova, Marina ; Quang, Dong Anh Khuong ; Fontebasso, Adam M. ; Stütz, Adrian M. ; Hutter, Sonja ; Zuckermann, Marc ; Sturm, Dominik ; Gronych, Jan ; Lasitschka, Bärbel ; Schmidt, Sabine ; Şeker-Cin, Huriye ; Witt, Hendrik ; Sultan, Marc ; Ralser, Meryem ; Northcott, Paul A. ; Hovestadt, Volker ; Bender, Sebastian ; Pfaff, Elke ; Stark, Sebastian ; Faury, Damien ; Schwartzentruber, Jeremy ; Majewski, Jacek ; Weber, Ursula D. ; Zapatka, Marc ; Raeder, Benjamin ; Schlesner, Matthias ; Worth, Catherine L. ; Bartholomae, Cynthia C. ; Von Kalle, Christof ; Imbusch, Charles D. ; Radomski, Sylwester ; Lawerenz, Chris ; Van Sluis, Peter ; Koster, Jan ; Volckmann, Richard ; Versteeg, Rogier ; Lehrach, Hans ; Monoranu, Camelia ; Winkler, Beate ; Unterberg, Andreas ; Mende, Christel Herold ; Milde, Till ; Kulozik, Andreas E. ; Ebinger, Martin ; Schuhmann, Martin U. ; Cho, Yoon Jae ; Pomeroy, Scott L. ; Von Deimling, Andreas ; Witt, Olaf ; Taylor, Michael D. ; Wolf, Stephan ; Karajannis, Matthias A. ; Eberhart, Charles G ; Scheurlen, Wolfram ; Hasselblatt, Martin ; Ligon, Keith L. ; Kieran, Mark W. ; Korbel, Jan O. ; Yaspo, Marie Laure ; Brors, Benedikt ; Felsberg, Jörg ; Reifenberger, Guido ; Collins, V. Peter ; Jabado, Nada ; Eils, Roland ; Lichter, Peter ; Pfister, Stefan M. / Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. In: Nature Genetics. 2013 ; Vol. 45, No. 8. pp. 927-932.
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abstract = "Pilocytic astrocytoma, the most common childhood brain tumor, is typically associated with mitogen-activated protein kinase (MAPK) pathway alterations. Surgically inaccessible midline tumors are therapeutically challenging, showing sustained tendency for progression and often becoming a chronic disease with substantial morbidities. Here we describe whole-genome sequencing of 96 pilocytic astrocytomas, with matched RNA sequencing (n = 73), conducted by the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. We identified recurrent activating mutations in FGFR1 and PTPN11 and new NTRK2 fusion genes in non-cerebellar tumors. New BRAF-activating changes were also observed. MAPK pathway alterations affected all tumors analyzed, with no other significant mutations identified, indicating that pilocytic astrocytoma is predominantly a single-pathway disease. Notably, we identified the same FGFR1 mutations in a subset of H3F3A-mutated pediatric glioblastoma with additional alterations in the NF1 gene. Our findings thus identify new potential therapeutic targets in distinct subsets of pilocytic astrocytoma and childhood glioblastoma.",
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AU - Kool, Marcel

AU - Warnatz, Hans Jörg

AU - Zichner, Thomas

AU - Lambert, Sally R.

AU - Ryzhova, Marina

AU - Quang, Dong Anh Khuong

AU - Fontebasso, Adam M.

AU - Stütz, Adrian M.

AU - Hutter, Sonja

AU - Zuckermann, Marc

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AU - Gronych, Jan

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AU - Schmidt, Sabine

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AU - Sultan, Marc

AU - Ralser, Meryem

AU - Northcott, Paul A.

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AU - Pfaff, Elke

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AU - Unterberg, Andreas

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AU - Pomeroy, Scott L.

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AU - Wolf, Stephan

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AU - Hasselblatt, Martin

AU - Ligon, Keith L.

AU - Kieran, Mark W.

AU - Korbel, Jan O.

AU - Yaspo, Marie Laure

AU - Brors, Benedikt

AU - Felsberg, Jörg

AU - Reifenberger, Guido

AU - Collins, V. Peter

AU - Jabado, Nada

AU - Eils, Roland

AU - Lichter, Peter

AU - Pfister, Stefan M.

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