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; 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 McCabe; 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

doi:10.1038/nature11284

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 WittmannMarc 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 McCabe, 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

566 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 language	English
Journal	Nature
Volume	488
Issue number	7409
Pages (from-to)	100-5
Number of pages	6
ISSN	0028-0836
DOIs	https://doi.org/10.1038/nature11284
Publication status	Published - 2 Aug 2012
Externally published	Yes

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Jones, D. T. W., Jäger, N., Kool, M., Zichner, T., Hutter, B., Sultan, M., Cho, Y.-J., Pugh, T. J., Hovestadt, V., Stütz, A. M., Rausch, T., Warnatz, H.-J., Ryzhova, M., Bender, S., Sturm, D., Pleier, S., Cin, H., Pfaff, E., Sieber, L., ... Lichter, P. (2012). Dissecting the genomic complexity underlying medulloblastoma. Nature, 488(7409), 100-5. https://doi.org/10.1038/nature11284

Jones, DTW, Jäger, N, Kool, M, Zichner, T, Hutter, B, Sultan, M, Cho, Y-J, Pugh, TJ, Hovestadt, V, Stütz, AM, Rausch, T, Warnatz, H-J, 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, Y-J, 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, McCabe, 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, M-L, Korbel, JO, Korshunov, A, Eils, R, Pfister, SM & Lichter, P 2012, 'Dissecting the genomic complexity underlying medulloblastoma', Nature, vol. 488, no. 7409, pp. 100-5. https://doi.org/10.1038/nature11284

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title = "Dissecting the genomic complexity underlying medulloblastoma",

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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doi = "10.1038/nature11284",

language = "English",

volume = "488",

pages = "100--5",

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TY - JOUR

T1 - Dissecting the genomic complexity underlying medulloblastoma

AU - Jones, David T W

AU - Jäger, Natalie

AU - Kool, Marcel

AU - Zichner, Thomas

AU - Hutter, Barbara

AU - Sultan, Marc

AU - Cho, Yoon-Jae

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

AU - Cin, Huriye

AU - Pfaff, Elke

AU - Sieber, Laura

AU - Wittmann, Andrea

AU - Remke, Marc

AU - Witt, Hendrik

AU - Hutter, Sonja

AU - Tzaridis, Theophilos

AU - Weischenfeldt, Joachim

AU - Raeder, Benjamin

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

AU - Shih, David

AU - Betts, Matthew J

AU - Russell, Robert B

AU - Coco, Simona

AU - Tonini, Gian Paolo

AU - Schüller, Ulrich

AU - Hans, Volkmar

AU - Graf, Norbert

AU - Kim, Yoo-Jin

AU - Monoranu, Camelia

AU - Roggendorf, Wolfgang

AU - Unterberg, Andreas

AU - Herold-Mende, Christel

AU - Milde, Till

AU - Kulozik, Andreas E

AU - von Deimling, Andreas

AU - Witt, Olaf

AU - Maass, Eberhard

AU - Rössler, Jochen

AU - Ebinger, Martin

AU - Schuhmann, Martin U

AU - Frühwald, Michael C

AU - Hasselblatt, Martin

AU - Jabado, Nada

AU - Rutkowski, Stefan

AU - von Bueren, André O

AU - Williamson, Dan

AU - Clifford, Steven C

AU - McCabe, Martin G

AU - Collins, V Peter

AU - Wolf, Stephan

AU - Wiemann, Stefan

AU - Lehrach, Hans

AU - Brors, Benedikt

AU - Scheurlen, Wolfram

AU - Felsberg, Jörg

AU - Reifenberger, Guido

AU - Northcott, Paul A

AU - Taylor, Michael D

AU - Meyerson, Matthew

AU - Pomeroy, Scott L

AU - Yaspo, Marie-Laure

AU - Korbel, Jan O

AU - Korshunov, Andrey

AU - Eils, Roland

AU - Pfister, Stefan M

AU - Lichter, Peter

PY - 2012/8/2

Y1 - 2012/8/2

N2 - 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.

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.

KW - Aging

KW - Amino Acid Sequence

KW - Cell Transformation, Neoplastic

KW - Cerebellar Neoplasms

KW - Child

KW - Chromatin

KW - Chromosomes, Human

KW - DEAD-box RNA Helicases

KW - DNA Helicases

KW - DNA-Binding Proteins

KW - Genome, Human

KW - Genomics

KW - Hedgehog Proteins

KW - High-Throughput Nucleotide Sequencing

KW - Histone Demethylases

KW - Humans

KW - Medulloblastoma

KW - Methylation

KW - Mutation

KW - Mutation Rate

KW - Neoplasm Proteins

KW - Nuclear Proteins

KW - Oncogene Proteins, Fusion

KW - Phosphoprotein Phosphatases

KW - Polyploidy

KW - Receptors, Cell Surface

KW - Sequence Analysis, RNA

KW - Signal Transduction

KW - T-Box Domain Proteins

KW - Transcription Factors

KW - Wnt Proteins

KW - beta Catenin

U2 - 10.1038/nature11284

DO - 10.1038/nature11284

M3 - Journal article

C2 - 22832583

SN - 0028-0836

VL - 488

SP - 100

EP - 105

JO - Nature

JF - Nature

IS - 7409

ER -

Dissecting the genomic complexity underlying medulloblastoma

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