Richard Kriwacki, Peter Lichter, Nada Jabado, Daniel Hübschmann, Nagarajan Paramasivam, Paul A. Northcott, Stefan M. Pfister, Benedikt Brors, Nina Thiessen, Andreas Von Deimling, Naveed Ishaque, Olaf Witt, Barbara Hutter, Matthias Schlesner, Kane Tse, Karen L. Mungall, Florence M. G. Cavalli, Yanling Liu, Nikos Sidiropoulos, Betty Luu, Christina Jäger-Schmidt, Matthias Bieg, Volker Hovestadt, Marina Ryzhova, Jaume Mora, Susanne Gröbner, Amar Gajjar, Eric Chuah, Martin Ebinger, Xiaochong Wu, Tobias Ehrenberger, Linda M. Liau, Vyacheslav Amstislavskiy, Kortine Kleinheinz, Jinghui Zhang, Ursula D. Weber, Michael Heinold, Maia Segura-Wang, Lukas Chavez, Ivo Buchhalter, David Finkelstein, Natalie Jäger, Michael D. Taylor, Andrey Korshunov, Steven J. M. Jones, Hans-Jörg Warnatz, Roland Eils, Marie-Laure Yaspo, Ernest Fraenkel, Christel Herold-Mende, David T. W. Jones, Alke Jugold, Jan O. Korbel, Yussanne Ma, Yoon-Jae Cho, Thomas Risch, Jan Koster, Vijay Ramaswamy, Stephan Wolf, A. Sorana Morrissy, Gang Wu, Marcel Kool, Vasilisa A. Rudneva, David Capper, Till Milde, Barbara C. Worst, Marc Zapatka, Serap Erkek, Toshihiro Kumabe, Scott L. Pomeroy, Sebastian M. Waszak, Aaron H. Phillips, Charles D. Imbusch, Tina Wong, Steven Schumacher, Andrew J. Mungall, Francisco German Rodriguez Gonzalez, Xin Zhou, Richard A. Moore, Zuguang Gu, Roger E. McLendon, Marco A. Marra, Joachim Weischenfeldt, Thomas Zichner, Martin Schuhmann, Giles W. Robinson, Rameen Beroukhim
Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and molecular processes that operate in medulloblastoma subgroups. Here we analyse the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 epigenetically analysed cases, and identify subgroup-specific driver alterations that include previously undiscovered actionable targets. Driver mutations were confidently assigned to most patients belonging to Group 3 and Group 4 medulloblastoma subgroups, greatly enhancing previous knowledge. New molecular subtypes were differentially enriched for specific driver events, including hotspot in-frame insertions that target KBTBD4 and ‘enhancer hijacking’ events that activate PRDM6. Thus, the application of integrative genomics to an extensive cohort of clinical samples derived from a single childhood cancer entity revealed a series of cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for the treatment of patients with medulloblastoma.
