Dissecting the genomic complexity underlying medulloblastoma

被引：648

作者：

Jones, David T. W. ^{[2
]}

Jaeger, Natalie ^{[1
]}

Kool, Marcel ^{[2
]}

Zichner, Thomas ^{[3
]}

Hutter, Barbara ^{[1
]}

Sultan, Marc ^{[4
]}

Cho, Yoon-Jae ^{[5
]}

Pugh, Trevor J. ^{[6
]}

Hovestadt, Volker ^{[7
]}

Stuetz, Adrian M. ^{[3
]}

Rausch, Tobias

Warnatz, Hans-Joerg ^{[4
]}

Ryzhova, Marina ^{[8
]}

Bender, Sebastian ^{[2
]}

Sturm, Dominik ^{[2
]}

Pleier, Sabrina ^{[2
]}

Cin, Huriye ^{[2
]}

Pfaff, Elke ^{[2
]}

Sieber, Laura ^{[2
]}

Wittmann, Andrea ^{[2
]}

Remke, Marc ^{[2
]}

Witt, Hendrik ^{[2
,9
]}

Hutter, Sonja ^{[2
]}

Tzaridis, Theophilos ^{[2
]}

Weischenfeldt, Joachim ^{[3
]}

Raeder, Benjamin ^{[3
]}

Avci, Meryem ^{[4
]}

Amstislavskiy, Vyacheslav ^{[4
]}

Zapatka, Marc ^{[7
]}

Weber, Ursula D. ^{[7
]}

Wang, Qi ^{[1
]}

Lasitschka, Baerbel

Bartholomae, Cynthia C. ^{[10
,11
]}

Schmidt, Manfred ^{[10
,11
]}

von Kalle, Christof ^{[10
,11
]}

Ast, Volker

Lawerenz, Chris

Eils, Juergen

Kabbe, Rolf ^{[1
]}

Benes, Vladimir

van Sluis, Peter ^{[12
]}

Koster, Jan ^{[12
]}

Volckmann, Richard ^{[12
]}

Shih, David ^{[13
]}

Betts, Matthew J. ^{[14
]}

Russell, Robert B. ^{[14
]}

Coco, Simona ^{[15
]}

Tonini, Gian Paolo ^{[15
]}

Schueller, Ulrich ^{[16
]}

Hans, Volkmar ^{[17
]}

机构：

[1] German Canc Res Ctr, Div Theoret Bioinformat, D-69120 Heidelberg, Germany

[2] German Canc Res Ctr, Div Pediat Neurooncol, D-69120 Heidelberg, Germany

[3] European Mol Biol Lab, D-69117 Heidelberg, Germany

[4] Max Planck Inst Mol Genet, D-14195 Berlin, Germany

[5] Stanford Univ, Div Child Neurol, Palo Alto, CA 94304 USA

[6] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[7] German Canc Res Ctr, Div Mol Genet, D-69120 Heidelberg, Germany

[8] NN Burdenko Inst Neurosurg, Dept Neuropathol, Moscow 125047, Russia

[9] Univ Heidelberg Hosp, Dept Pediat Oncol Hematol & Immunol, D-69120 Heidelberg, Germany

[10] German Canc Res Ctr, Div Translat Oncol, D-69120 Heidelberg, Germany

[11] Natl Ctr Tumor Dis NCT, D-69120 Heidelberg, Germany

[12] Univ Amsterdam, AMC, Dept Oncogenom, NL-1105 AZ Amsterdam, Netherlands

[13] Hosp Sick Children, Arthur & Sonia Labbatt Brain Tumor Res Ctr, Toronto, ON M5G 1X8, Canada

[14] Heidelberg Univ, Cell Networks Cluster Excellence, D-69120 Heidelberg, Germany

[15] IRCCS Azienda Osped Univ San Martino, IST Ist Nazl Ric Canc, Dept Adv Diagnost Technol, I-16132 Genoa, Italy

[16] Univ Munich, Ctr Neuropathol & Prion Res, D-81377 Munich, Germany

[17] Evangel Krankenhaus, Inst Neuropathol, D-33617 Bielefeld, Germany

[18] Saarland Univ Hosp, Dept Paediat Oncol & Haematol, D-66421 Homburg, Germany

[19] Saarland Univ Hosp, Inst Pathol, D-66424 Homburg, Germany

[20] Inst Pathol, Dept Neuropathol, D-97080 Wurzburg, Germany

[21] Univ Heidelberg Hosp, Dept Neurosurg, D-69120 Heidelberg, Germany

[22] German Canc Res Ctr, Clin Cooperat Unit Pediat Oncol, D-69120 Heidelberg, Germany

[23] Heidelberg Univ, Dept Neuropathol, D-69120 Heidelberg, Germany

[24] German Canc Res Ctr, Clin Cooperat Unit Neuropathol, D-69120 Heidelberg, Germany

[25] Klinikum Stuttgart Olgahosp, Dept Pediat Oncol Hematol & Immunol, D-70176 Stuttgart, Germany

[26] Univ Hosp Freiburg, Dept Paediat Haematol & Oncol, D-79106 Freiburg, Germany

[27] Childrens Univ Hosp, Dept Hematol & Oncol, D-72076 Tubingen, Germany

[28] Univ Hosp, Dept Neurosurg, D-72076 Tubingen, Germany

[29] Childrens Hosp Augsburg, D-86156 Augsburg, Germany

[30] Univ Hosp Munster, Inst Neuropathol, D-48149 Munster, Germany

[31] McGill Univ, Dept Pediat, Montreal, PQ H3Z 2Z3, Canada

[32] McGill Univ, Dept Human Genet, Montreal, PQ H3Z 2Z3, Canada

[33] McGill Univ Hlth Ctr Res Inst, Montreal, PQ H3Z 2Z3, Canada

[34] Univ Med Ctr Hamburg Eppendorf, Dept Paediat Haematol & Oncol, D-20246 Hamburg, Germany

[35] Newcastle Univ, Royal Victoria Infirm, No Inst Canc Res, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England

[36] Univ Manchester, Manchester Acad Hlth Sci Ctr, Sch Canc & Enabling Sci, Manchester M13 9PL, Lancs, England

[37] Univ Cambridge, Dept Pathol, Div Mol Histopathol, Cambridge CB2 0QQ, England

[38] German Canc Res Ctr, Div Mol Genome Anal, D-69120 Heidelberg, Germany

[39] Nurnberg Childrens Hosp, Cnopfsche Kinderklinik, D-90419 Nurnberg, Germany

[40] Univ Dusseldorf, Dept Neuropathol, D-40225 Dusseldorf, Germany

[41] Hosp Sick Children, Div Neurosurg, Toronto, ON M5G 1X8, Canada

[42] Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON M5G 1X8, Canada

[43] Dana Farber Canc Inst, Boston, MA 02215 USA

[44] Childrens Hosp, Boston, MA 02115 USA

[45] Heidelberg Univ, Inst Pharm & Mol Biotechnol, D-69120 Heidelberg, Germany

[46] Heidelberg Univ, Bioquant Ctr, D-69120 Heidelberg, Germany

来源：

NATURE | 2012年 / 488卷 / 7409期

关键词：

TETRAPLOID TUMOR-CELLS; MUTATIONS; ACTIVATION; SUBGROUPS; LANDSCAPE; GENES; TBR1;

D O I：

10.1038/nature11284

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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(1). 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(2,3). WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens(4). SHH tumours show hedgehog pathway activation, and have an intermediate prognosis(2). Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges(2,3,5). 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.

引用

页码：100 / 105

页数：6

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