Dissecting the genomic complexity underlying medulloblastoma

David T.W. Jones, Natalie Jäger, Marcel Kool, Thomas Zichner, Barbara Hutter, Marc Sultan, Yoon-Jae Cho, Trevor J. Pugh, Volker Hovestadt, Adrian M. Stütz, Tobias Rausch, Hans Jörg Warnatz, Marina Ryzhova, Sebastian Bender, Dominik Sturm, Sabrina Pleier, Huriye Cin, Elke Pfaff, Laura Sieber, Andrea Wittmann & 70 others Marc Remke, Hendrik Witt, Sonja Hutter, Theophilos Tzaridis, Joachim Weischenfeldt, Benjamin Raeder, Meryem Avci, Vyacheslav Amstislavskiy, Marc Zapatka, Ursula D. Weber, Qi Wang, Bärbel Lasitschka, Cynthia C. Bartholomae, Manfred Schmidt, Christof von Kalle, Volker Ast, Chris Lawerenz, Jürgen Eils, Rolf Kabbe, Vladimir Benes, Peter van Sluis, Jan Koster, Richard Volckmann, David Shih, Matthew J. Betts, Robert B. Russell, Simona Coco, Gian Paolo Tonini, Ulrich Schüller, Volkmar Hans, Norbert Graf, Yoo Jin Kim, Camelia Monoranu, Wolfgang Roggendorf, Andreas Unterberg, Christel Herold-Mende, Till Milde, Andreas E. Kulozik, Andreas von Deimling, Olaf Witt, Eberhard Maass, Jochen Rössler, Martin Ebinger, Martin U. Schuhmann, Michael C. Frühwald, Martin Hasselblatt, Nada Jabado, Stefan Rutkowski, André O. von Bueren, Dan Williamson, Steven C. Clifford, Martin G. Mc Cabe, V. Peter Collins, Stephan Wolf, Stefan Wiemann, Hans Lehrach, Benedikt Brors, Wolfram Scheurlen, Jörg Felsberg, Guido Reifenberger, Paul A. Northcott, Michael D. Taylor, Matthew Meyerson, Scott L. Pomeroy, Marie Laure Yaspo, Jan O. Korbel, Andrey Korshunov, Roland Eils, Stefan M. Pfister, Peter Lichter

Research output: Contribution to journalArticle

481 Citations (Scopus)

Abstract

Medulloblastoma is an aggressively growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and shows tremendous biological and clinical heterogeneity. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently identified. WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis. Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges. The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour-normal pairs, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. Tetraploidy was identified as a frequent early event in Group 3 and 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA sequencing confirmed these alterations, and revealed the expression of what are, to our knowledge, the first medulloblastoma fusion genes identified. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 and 4 patients.

Original languageEnglish (US)
Pages (from-to)100-105
Number of pages6
JournalNature
Volume488
Issue number7409
DOIs
StatePublished - Aug 2 2012
Externally publishedYes

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Medulloblastoma
Neoplasms
RNA Sequence Analysis
High-Throughput Nucleotide Sequencing
Tetraploidy
Gene Fusion
Mutation Rate
Brain Neoplasms
Cerebellum
Genes
Brain Stem
Chromatin
Therapeutics
Quality of Life
Genome

ASJC Scopus subject areas

  • General

Cite this

Jones, D. T. W., Jäger, N., Kool, M., Zichner, T., Hutter, B., Sultan, M., ... Lichter, P. (2012). Dissecting the genomic complexity underlying medulloblastoma. Nature, 488(7409), 100-105. https://doi.org/10.1038/nature11284

Dissecting the genomic complexity underlying medulloblastoma. / Jones, David T.W.; Jäger, Natalie; Kool, Marcel; Zichner, Thomas; Hutter, Barbara; Sultan, Marc; Cho, Yoon-Jae; Pugh, Trevor J.; Hovestadt, Volker; Stütz, Adrian M.; Rausch, Tobias; Warnatz, Hans Jörg; Ryzhova, Marina; Bender, Sebastian; Sturm, Dominik; Pleier, Sabrina; Cin, Huriye; Pfaff, Elke; Sieber, Laura; Wittmann, Andrea; Remke, Marc; Witt, Hendrik; Hutter, Sonja; Tzaridis, Theophilos; Weischenfeldt, Joachim; Raeder, Benjamin; Avci, Meryem; Amstislavskiy, Vyacheslav; Zapatka, Marc; Weber, Ursula D.; Wang, Qi; Lasitschka, Bärbel; Bartholomae, Cynthia C.; Schmidt, Manfred; von Kalle, Christof; Ast, Volker; Lawerenz, Chris; Eils, Jürgen; Kabbe, Rolf; Benes, Vladimir; van Sluis, Peter; Koster, Jan; Volckmann, Richard; Shih, David; Betts, Matthew J.; Russell, Robert B.; Coco, Simona; Tonini, Gian Paolo; Schüller, Ulrich; Hans, Volkmar; Graf, Norbert; Kim, Yoo Jin; Monoranu, Camelia; Roggendorf, Wolfgang; Unterberg, Andreas; Herold-Mende, Christel; Milde, Till; Kulozik, Andreas E.; von Deimling, Andreas; Witt, Olaf; Maass, Eberhard; Rössler, Jochen; Ebinger, Martin; Schuhmann, Martin U.; Frühwald, Michael C.; Hasselblatt, Martin; Jabado, Nada; Rutkowski, Stefan; von Bueren, André O.; Williamson, Dan; Clifford, Steven C.; Mc Cabe, Martin G.; Collins, V. Peter; Wolf, Stephan; Wiemann, Stefan; Lehrach, Hans; Brors, Benedikt; Scheurlen, Wolfram; Felsberg, Jörg; Reifenberger, Guido; Northcott, Paul A.; Taylor, Michael D.; Meyerson, Matthew; Pomeroy, Scott L.; Yaspo, Marie Laure; Korbel, Jan O.; Korshunov, Andrey; Eils, Roland; Pfister, Stefan M.; Lichter, Peter.

In: Nature, Vol. 488, No. 7409, 02.08.2012, p. 100-105.

Research output: Contribution to journalArticle

Jones, DTW, Jäger, N, Kool, M, Zichner, T, Hutter, B, Sultan, M, Cho, Y-J, Pugh, TJ, Hovestadt, V, Stütz, AM, Rausch, T, Warnatz, HJ, Ryzhova, M, Bender, S, Sturm, D, Pleier, S, Cin, H, Pfaff, E, Sieber, L, Wittmann, A, Remke, M, Witt, H, Hutter, S, Tzaridis, T, Weischenfeldt, J, Raeder, B, Avci, M, Amstislavskiy, V, Zapatka, M, Weber, UD, Wang, Q, Lasitschka, B, Bartholomae, CC, Schmidt, M, von Kalle, C, Ast, V, Lawerenz, C, Eils, J, Kabbe, R, Benes, V, van Sluis, P, Koster, J, Volckmann, R, Shih, D, Betts, MJ, Russell, RB, Coco, S, Tonini, GP, Schüller, U, Hans, V, Graf, N, Kim, YJ, Monoranu, C, Roggendorf, W, Unterberg, A, Herold-Mende, C, Milde, T, Kulozik, AE, von Deimling, A, Witt, O, Maass, E, Rössler, J, Ebinger, M, Schuhmann, MU, Frühwald, MC, Hasselblatt, M, Jabado, N, Rutkowski, S, von Bueren, AO, Williamson, D, Clifford, SC, Mc Cabe, MG, Collins, VP, Wolf, S, Wiemann, S, Lehrach, H, Brors, B, Scheurlen, W, Felsberg, J, Reifenberger, G, Northcott, PA, Taylor, MD, Meyerson, M, Pomeroy, SL, Yaspo, ML, Korbel, JO, Korshunov, A, Eils, R, Pfister, SM & Lichter, P 2012, 'Dissecting the genomic complexity underlying medulloblastoma', Nature, vol. 488, no. 7409, pp. 100-105. https://doi.org/10.1038/nature11284
Jones DTW, Jäger N, Kool M, Zichner T, Hutter B, Sultan M et al. Dissecting the genomic complexity underlying medulloblastoma. Nature. 2012 Aug 2;488(7409):100-105. https://doi.org/10.1038/nature11284
Jones, David T.W. ; Jäger, Natalie ; Kool, Marcel ; Zichner, Thomas ; Hutter, Barbara ; Sultan, Marc ; Cho, Yoon-Jae ; Pugh, Trevor J. ; Hovestadt, Volker ; Stütz, Adrian M. ; Rausch, Tobias ; Warnatz, Hans Jörg ; Ryzhova, Marina ; Bender, Sebastian ; Sturm, Dominik ; Pleier, Sabrina ; Cin, Huriye ; Pfaff, Elke ; Sieber, Laura ; Wittmann, Andrea ; Remke, Marc ; Witt, Hendrik ; Hutter, Sonja ; Tzaridis, Theophilos ; Weischenfeldt, Joachim ; Raeder, Benjamin ; Avci, Meryem ; Amstislavskiy, Vyacheslav ; Zapatka, Marc ; Weber, Ursula D. ; Wang, Qi ; Lasitschka, Bärbel ; Bartholomae, Cynthia C. ; Schmidt, Manfred ; von Kalle, Christof ; Ast, Volker ; Lawerenz, Chris ; Eils, Jürgen ; Kabbe, Rolf ; Benes, Vladimir ; van Sluis, Peter ; Koster, Jan ; Volckmann, Richard ; Shih, David ; Betts, Matthew J. ; Russell, Robert B. ; Coco, Simona ; Tonini, Gian Paolo ; Schüller, Ulrich ; Hans, Volkmar ; Graf, Norbert ; Kim, Yoo Jin ; Monoranu, Camelia ; Roggendorf, Wolfgang ; Unterberg, Andreas ; Herold-Mende, Christel ; Milde, Till ; Kulozik, Andreas E. ; von Deimling, Andreas ; Witt, Olaf ; Maass, Eberhard ; Rössler, Jochen ; Ebinger, Martin ; Schuhmann, Martin U. ; Frühwald, Michael C. ; Hasselblatt, Martin ; Jabado, Nada ; Rutkowski, Stefan ; von Bueren, André O. ; Williamson, Dan ; Clifford, Steven C. ; Mc Cabe, Martin G. ; Collins, V. Peter ; Wolf, Stephan ; Wiemann, Stefan ; Lehrach, Hans ; Brors, Benedikt ; Scheurlen, Wolfram ; Felsberg, Jörg ; Reifenberger, Guido ; Northcott, Paul A. ; Taylor, Michael D. ; Meyerson, Matthew ; Pomeroy, Scott L. ; Yaspo, Marie Laure ; Korbel, Jan O. ; Korshunov, Andrey ; Eils, Roland ; Pfister, Stefan M. ; Lichter, Peter. / Dissecting the genomic complexity underlying medulloblastoma. In: Nature. 2012 ; Vol. 488, No. 7409. pp. 100-105.
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abstract = "Medulloblastoma is an aggressively growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and shows tremendous biological and clinical heterogeneity. Despite recent treatment advances, approximately 40{\%} of children experience tumour recurrence, and 30{\%} will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently identified. WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis. Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges. The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour-normal pairs, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. Tetraploidy was identified as a frequent early event in Group 3 and 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA sequencing confirmed these alterations, and revealed the expression of what are, to our knowledge, the first medulloblastoma fusion genes identified. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 and 4 patients.",
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AU - Hutter, Barbara

AU - Sultan, Marc

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AU - Pugh, Trevor J.

AU - Hovestadt, Volker

AU - Stütz, Adrian M.

AU - Rausch, Tobias

AU - Warnatz, Hans Jörg

AU - Ryzhova, Marina

AU - Bender, Sebastian

AU - Sturm, Dominik

AU - Pleier, Sabrina

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AU - Wittmann, Andrea

AU - Remke, Marc

AU - Witt, Hendrik

AU - Hutter, Sonja

AU - Tzaridis, Theophilos

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AU - Avci, Meryem

AU - Amstislavskiy, Vyacheslav

AU - Zapatka, Marc

AU - Weber, Ursula D.

AU - Wang, Qi

AU - Lasitschka, Bärbel

AU - Bartholomae, Cynthia C.

AU - Schmidt, Manfred

AU - von Kalle, Christof

AU - Ast, Volker

AU - Lawerenz, Chris

AU - Eils, Jürgen

AU - Kabbe, Rolf

AU - Benes, Vladimir

AU - van Sluis, Peter

AU - Koster, Jan

AU - Volckmann, Richard

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AU - Betts, Matthew J.

AU - Russell, Robert B.

AU - Coco, Simona

AU - Tonini, Gian Paolo

AU - Schüller, Ulrich

AU - Hans, Volkmar

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AU - Kim, Yoo Jin

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AU - Schuhmann, Martin U.

AU - Frühwald, Michael C.

AU - Hasselblatt, Martin

AU - Jabado, Nada

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AU - von Bueren, André O.

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AU - Clifford, Steven C.

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AU - Brors, Benedikt

AU - Scheurlen, Wolfram

AU - Felsberg, Jörg

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AU - Korbel, Jan O.

AU - Korshunov, Andrey

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AU - Lichter, Peter

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AB - Medulloblastoma is an aggressively growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and shows tremendous biological and clinical heterogeneity. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently identified. WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis. Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges. The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour-normal pairs, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. Tetraploidy was identified as a frequent early event in Group 3 and 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA sequencing confirmed these alterations, and revealed the expression of what are, to our knowledge, the first medulloblastoma fusion genes identified. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 and 4 patients.

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