Subgroup-specific structural variation across 1,000 medulloblastoma genomes

Paul A. Northcott, David J.H. Shih, John Peacock, Livia Garzia, A. Sorana Morrissy, Thomas Zichner, Adrian M. Stútz, Andrey Korshunov, Júri Reimand, Steven E. Schumacher, Rameen Beroukhim, David W. Ellison, Christian R. Marshall, Anath C. Lionel, Stephen MacK, Adrian Dubuc, Yuan Yao, Vijay Ramaswamy, Betty Luu, Adi RoliderFlorence M.G. Cavalli, Xin Wang, Marc Remke, Xiaochong Wu, Readman Y.B. Chiu, Andy Chu, Eric Chuah, Richard D. Corbett, Gemma R. Hoad, Shaun D. Jackman, Yisu Li, Allan Lo, Karen L. Mungall, Ka Ming Nip, Jenny Q. Qian, Anthony G.J. Raymond, Nina Thiessen, Richard J. Varhol, Inanc Birol, Richard A. Moore, Andrew J. Mungall, Robert Holt, Daisuke Kawauchi, Martine F. Roussel, Marcel Kool, David T.W. Jones, Hendrick Witt, Africa Fernandez-L, Anna M. Kenney, Robert J. Wechsler-Reya, Peter Dirks, Tzvi Aviv, Wieslawa A. Grajkowska, Marta Perek-Polnik, Christine C. Haberler, Olivier Delattre, Stéphanie S. Reynaud, François F. Doz, Sarah S. Pernet-Fattet, Byung Kyu Cho, Seung Ki Kim, Kyu Chang Wang, Wolfram Scheurlen, Charles G. Eberhart, Michelle Fèvre-Montange, Anne Jouvet, Ian F. Pollack, Xing Fan, Karin M. Muraszko, G. Yancey Gillespie, Concezio Di Rocco, Luca Massimi, Erna M.C. Michiels, Nanne K. Kloosterhof, Pim J. French, Johan M. Kros, James M. Olson, Richard G. Ellenbogen, Karel Zitterbart, Leos Kren, Reid C. Thompson, Michael K. Cooper, Boleslaw Lach, Roger E. McLendon, Darell D. Bigner, Adam Fontebasso, Steffen Albrecht, Nada Jabado, Janet C. Lindsey, Simon Bailey, Nalin Gupta, William A. Weiss, László Bognár, Almos Klekner, Timothy E. Van Meter, Toshihiro Kumabe, Teiji Tominaga, Samer K. Elbabaa, Jeffrey R. Leonard, Joshua B. Rubin, Linda M. Liau, Erwin G. Van Meir, Maryam Fouladi, Hideo Nakamura, Giuseppe Cinalli, Miklós Garami, Peter Hauser, Ali G. Saad, Achille Iolascon, Shin Jung, Carlos G. Carlotti, Rajeev Vibhakar, Young Shin Ra, Shenandoah Robinson, Massimo Zollo, Claudia C. Faria, Jennifer A. Chan, Michael L. Levy, Poul H.B. Sorensen, Matthew Meyerson, Scott L. Pomeroy, Yoon Jae Cho, Gary D. Bader, Uri Tabori, Cynthia E. Hawkins, Eric Bouffet, Stephen W. Scherer, James T. Rutka, David Malkin, Steven C. Clifford, Steven J.M. Jones, Jan O. Korbel, Stefan M. Pfister, Marco A. Marra, Michael D. Taylor

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Abstract

Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy.

Original languageEnglish
Pages (from-to)49-56
Number of pages8
JournalNature
Volume487
Issue number7409
DOIs
Publication statusPublished - 2012 Aug 2

ASJC Scopus subject areas

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    Northcott, P. A., Shih, D. J. H., Peacock, J., Garzia, L., Sorana Morrissy, A., Zichner, T., Stútz, A. M., Korshunov, A., Reimand, J., Schumacher, S. E., Beroukhim, R., Ellison, D. W., Marshall, C. R., Lionel, A. C., MacK, S., Dubuc, A., Yao, Y., Ramaswamy, V., Luu, B., ... Taylor, M. D. (2012). Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature, 487(7409), 49-56. https://doi.org/10.1038/nature11327