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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.

SUBMITTER: Jones DT

PROVIDER: S-EPMC3662966 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Dissecting the genomic complexity underlying medulloblastoma.

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

Nature 20120801 7409

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 ar ...[more]

PMID: 22832583

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Dissecting the genomic complexity underlying medulloblastoma.

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Dissecting the genomic complexity underlying medulloblastoma.

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