Subgroup-specific structural variation across 1,000 medulloblastoma genomes

PA Northcott, DJH Shih, J Peacock, L Garzia, AS Morrissy, T Zichner, AM Stutz, A Korshunov, J Reimand, SE Schumacher, R Beroukhim, DW Ellison, CR Marshall, AC Lionel, S Mack, A Dubuc, Y Yao, V Ramaswamy, B Luu, A RoliderFMG Cavalli, X Wang, M Remke, XC Wu, RYB Chiu, A Chu, E Chuah, RD Corbett, GR Hoad, SD Jackman, YS Li, A Lo, KL Mungall, KM Nip, JQ Qian, AGJ Raymond, N Thiessen, RJ Varhol, I Birol, RA Moore, AJ Mungall, R van der Holt, D Kawauchi, MF Roussel, Mirjam Kool, DTW Jones, H Witt, A Fernandez-L, AM Kenney, RJ Wechsler-Reya, P Dirks, T Aviv, WA Grajkowska, M Perek-Polnik, CC Haberler, O Delattre, SS Reynaud, FF Doz, SS Pernet-Fattet, BK Cho, SK Kim, KC Wang, W Scheurlen, CG Eberhart, M Fevre-Montange, A Jouvet, IF Pollack, X Fan, KM Muraszko, GY Gillespie, C Di Rocco, L Massimi, Erna Michiels, Nanne Kloosterhof, Pim French, J.M. Kros, JM Olson, RG Ellenbogen, K Zitterbart, L Kren, RC Thompson, MK Cooper, B Lach, RE McLendon, DD Bigner, A Fontebasso, S Albrecht, N Jabado, JC Lindsey, S Bailey, N Gupta, WA Weiss, L Bognar, A Klekner, TE Van Meter, T Kumabe, T Tominaga, SK Elbabaa, JR Leonard, JB Rubin, LM Liau, EG van Meir, M Fouladi, H Nakamura, G Cinalli, M Garami, P Hauser, AG Saad, A Iolascon, S Jung, CG Carlotti, R Vibhakar, YS Ra, S Robinson, M Zollo, CC Faria, JA Chan, ML Levy, PHB Sorensen, M Meyerson, SL Pomeroy, YJ Cho, GD Bader, U Tabori, CE Hawkins, E Bouffet, SW Scherer, JT Rutka, D Malkin, SC Clifford, SJM Jones, JO Korbel, SM Pfister, MA Marra, MD Taylor

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615 Citations (Scopus)

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 4 alpha. 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-beta signalling in Group 3, and NF-kappa B signalling in Group 4, suggest future avenues for rational, targeted therapy.
Original languageEnglish
Pages (from-to)49-56
Number of pages8
JournalNature
Volume488
Issue number7409
DOIs
Publication statusPublished - 2012

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