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 von Bueren; O André; 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

Dissecting the genomic complexity underlying medulloblastoma.

Standard

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; André, O; Williamson, Dan; Clifford, Steven C; McCabe, 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, 7409, 2012, p. 100-105.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

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, A, André, O, 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, 7409, pp. 100-105. <http://www.ncbi.nlm.nih.gov/pubmed/22832583?dopt=Citation>

APA

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), 100-105. [7409]. http://www.ncbi.nlm.nih.gov/pubmed/22832583?dopt=Citation

Vancouver

Jones DTW, Jäger N, Kool M, Zichner T, Hutter B, Sultan M et al. Dissecting the genomic complexity underlying medulloblastoma. NATURE. 2012;488(7409):100-105. 7409.

Bibtex

@article{75e471cebec54250b1b3007dd6f7a242,

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.",

keywords = "Humans, Child, Cell Transformation, Neoplastic, Amino Acid Sequence, Signal Transduction, Methylation, Genomics, Mutation/genetics, beta Catenin/genetics, DNA-Binding Proteins/genetics, Nuclear Proteins/genetics, Wnt Proteins/metabolism, Mutation Rate, Oncogene Proteins, Fusion/genetics, Polyploidy, Transcription Factors/genetics, Aging/genetics, Cerebellar Neoplasms/classification/diagnosis/*genetics/pathology, Chromatin/metabolism, Chromosomes, Human/genetics, DEAD-box RNA Helicases/genetics, DNA Helicases/genetics, Genome, Human/*genetics, Hedgehog Proteins/metabolism, High-Throughput Nucleotide Sequencing, Histone Demethylases/genetics, Medulloblastoma/classification/diagnosis/*genetics/pathology, Neoplasm Proteins/genetics, Phosphoprotein Phosphatases/genetics, Receptors, Cell Surface/genetics, Sequence Analysis, RNA, T-Box Domain Proteins/genetics, Humans, Child, Cell Transformation, Neoplastic, Amino Acid Sequence, Signal Transduction, Methylation, Genomics, Mutation/genetics, beta Catenin/genetics, DNA-Binding Proteins/genetics, Nuclear Proteins/genetics, Wnt Proteins/metabolism, Mutation Rate, Oncogene Proteins, Fusion/genetics, Polyploidy, Transcription Factors/genetics, Aging/genetics, Cerebellar Neoplasms/classification/diagnosis/*genetics/pathology, Chromatin/metabolism, Chromosomes, Human/genetics, DEAD-box RNA Helicases/genetics, DNA Helicases/genetics, Genome, Human/*genetics, Hedgehog Proteins/metabolism, High-Throughput Nucleotide Sequencing, Histone Demethylases/genetics, Medulloblastoma/classification/diagnosis/*genetics/pathology, Neoplasm Proteins/genetics, Phosphoprotein Phosphatases/genetics, Receptors, Cell Surface/genetics, Sequence Analysis, RNA, T-Box Domain Proteins/genetics",

author = "Jones, {David T W} and Natalie J{\"a}ger and Marcel Kool and Thomas Zichner and Barbara Hutter and Marc Sultan and Yoon-Jae Cho and Pugh, {Trevor J} and Volker Hovestadt and St{\"u}tz, {Adrian M} and Tobias Rausch and Hans-J{\"o}rg Warnatz and Marina Ryzhova and Sebastian Bender and Dominik Sturm and Sabrina Pleier and Huriye Cin and Elke Pfaff and Laura Sieber and Andrea Wittmann and Marc Remke and Hendrik Witt and Sonja Hutter and Theophilos Tzaridis and Joachim Weischenfeldt and Benjamin Raeder and Meryem Avci and Vyacheslav Amstislavskiy and Marc Zapatka and Weber, {Ursula D} and Qi Wang and B{\"a}rbel Lasitschka and Bartholomae, {Cynthia C} and Manfred Schmidt and {von Kalle}, Christof and Volker Ast and Chris Lawerenz and J{\"u}rgen Eils and Rolf Kabbe and Vladimir Benes and {van Sluis}, Peter and Jan Koster and Richard Volckmann and David Shih and Betts, {Matthew J} and Russell, {Robert B} and Simona Coco and Tonini, {Gian Paolo} and Ulrich Sch{\"u}ller and Volkmar Hans and Norbert Graf and Yoo-Jin Kim and Camelia Monoranu and Wolfgang Roggendorf and Andreas Unterberg and Christel Herold-Mende and Till Milde and Kulozik, {Andreas E} and {von Deimling}, Andreas and Olaf Witt and Eberhard Maass and Jochen R{\"o}ssler and Martin Ebinger and Schuhmann, {Martin U} and Fr{\"u}hwald, {Michael C} and Martin Hasselblatt and Nada Jabado and Stefan Rutkowski and {von Bueren}, Andr{\'e} and O Andr{\'e} and Dan Williamson and Clifford, {Steven C} and McCabe, {Martin G} and Collins, {V Peter} and Stephan Wolf and Stefan Wiemann and Hans Lehrach and Benedikt Brors and Wolfram Scheurlen and J{\"o}rg Felsberg and Guido Reifenberger and Northcott, {Paul A} and Taylor, {Michael D} and Matthew Meyerson and Pomeroy, {Scott L} and Marie-Laure Yaspo and Korbel, {Jan O} and Andrey Korshunov and Roland Eils and Pfister, {Stefan M} and Peter Lichter",

year = "2012",

language = "English",

volume = "488",

pages = "100--105",

journal = "NATURE",

issn = "0028-0836",

publisher = "NATURE PUBLISHING GROUP",

number = "7409",

}

RIS

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

AU - 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

Y1 - 2012

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 - Humans

KW - Child

KW - Cell Transformation, Neoplastic

KW - Amino Acid Sequence

KW - Signal Transduction

KW - Methylation

KW - Genomics

KW - Mutation/genetics

KW - beta Catenin/genetics

KW - DNA-Binding Proteins/genetics

KW - Nuclear Proteins/genetics

KW - Wnt Proteins/metabolism

KW - Mutation Rate

KW - Oncogene Proteins, Fusion/genetics

KW - Polyploidy

KW - Transcription Factors/genetics

KW - Aging/genetics

KW - Cerebellar Neoplasms/classification/diagnosis/genetics/pathology

KW - Chromatin/metabolism

KW - Chromosomes, Human/genetics

KW - DEAD-box RNA Helicases/genetics

KW - DNA Helicases/genetics

KW - Genome, Human/genetics

KW - Hedgehog Proteins/metabolism

KW - High-Throughput Nucleotide Sequencing

KW - Histone Demethylases/genetics

KW - Medulloblastoma/classification/diagnosis/genetics/pathology

KW - Neoplasm Proteins/genetics

KW - Phosphoprotein Phosphatases/genetics

KW - Receptors, Cell Surface/genetics

KW - Sequence Analysis, RNA

KW - T-Box Domain Proteins/genetics