Dissecting the genomic complexity underlying medulloblastoma

• Published in: Nature (London) 2012-08, Vol.488 (7409), p.100-105
• Main Authors: 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, Paolo Tonini, Gian, 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., McCabe, Martin G., Peter Collins, V., 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
• Format: Article
• Language: English
• Subjects: 631/1647/2217; 631/208/68; 631/67/1922; 631/67/2332; Aging - genetics; Amino Acid Sequence; beta Catenin - genetics; Cancer; Cell Transformation, Neoplastic; Cerebellar Neoplasms - classification; Cerebellar Neoplasms - diagnosis; Cerebellar Neoplasms - genetics; Cerebellar Neoplasms - pathology; Child; Chromatin - metabolism; Chromosomes, Human - genetics; DEAD-box RNA Helicases - genetics; Development and progression; DNA Helicases - genetics; DNA-Binding Proteins - genetics; Genetic aspects; Genome, Human - genetics; Genomics; Hedgehog Proteins - metabolism; High-Throughput Nucleotide Sequencing; Histone Demethylases - genetics; Humanities and Social Sciences; Humans; letter; Medulloblastoma; Medulloblastoma - classification; Medulloblastoma - diagnosis; Medulloblastoma - genetics; Medulloblastoma - pathology; Metastasis; Methylation; multidisciplinary; Mutation - genetics; Mutation Rate; Neoplasm Proteins - genetics; Nuclear Proteins - genetics; Oncogene Proteins, Fusion - genetics; Patched Receptors; Patched-1 Receptor; Phosphoprotein Phosphatases - genetics; Physiological aspects; Polyploidy; Receptors, Cell Surface - genetics; Science; Science (multidisciplinary); Sequence Analysis, RNA; Signal Transduction; T-Box Domain Proteins - genetics; Transcription Factors - genetics; Wnt Proteins - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature11284

Medulloblastoma is the most common brain tumour in children; using whole-genome sequencing of tumour samples the authors show that the clinically challenging Group 3 and 4 tumours can be tetraploid, and reveal the expression of the first medulloblastoma fusion genes identified. The medulloblastoma genome dissected Medulloblastoma is the most common malignant brain tumour in children. Four papers published in the 2 August 2012 issue of Nature use whole-genome and other sequencing techniques to produce a detailed picture of the genetics and genomics of this condition. Notable findings include the identification of recurrent mutations in genes not previously implicated in medulloblastoma, with significant genetic differences associated with the four biologically distinct subgroups and clinical outcomes in each. Potential avenues for therapy are suggested by the identification of targetable somatic copy-number alterations, including recurrent events targeting TGFβ signalling in Group 3, and NF-κB signalling in Group 4 medulloblastomas. 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 l