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. 2012 Aug 2;488(7409):49-56.
doi: 10.1038/nature11327.

Subgroup-specific structural variation across 1,000 medulloblastoma genomes

Paul A Northcott  1 , David J H Shih, John Peacock, Livia Garzia, A Sorana Morrissy, Thomas Zichner, Adrian M Stütz, Andrey Korshunov, Jüri 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 Rolider, Florence 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 T 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
Affiliations

Subgroup-specific structural variation across 1,000 medulloblastoma genomes

Paul A Northcott et al. Nature. .

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.

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Figures

Figure 1
Figure 1. Genomic heterogeneity of medulloblastoma subgroups
a, The medulloblastoma genome classified by subgroup. b, Frequency and significance (q-value≤ 0.1) of broad cytogenetic events across medulloblastoma subgroups. c, Significant regions of focal SCNA identified by GISTIC2 in either pan-cohort or subgroup-specific analyses. d, e, Recurrent high-level amplifications (d; segmented CN≥5) and homozygous deletions (e; segmented CN≤0.7) in medulloblastoma. The number of genes mapping to the GISTIC2 peak region (where applicable) is listed in brackets after the suspected driver gene, as is the frequency of each event.
Figure 2
Figure 2. Genomic alterations affect core signaling pathways in SHH medulloblastoma
a, GISTIC2 significance plot of amplifications (red) and deletions (blue) observed in SHH. The number of genes mapping to each significant region are included in brackets and regions enriched in SHH are shaded red. b, c, Recurrent amplifications of PPM1D (b) and PIK3C2B/MDM4 (c) are restricted to SHH. d, FISH validation of MDM4 amplification. e, SHH signaling, TP53 signaling, and RTK/PI3K signaling represent the core pathways genomically targeted in SHH. P-values indicate the prevalence with which the respective pathway is targeted in SHH vs. non-SHH cases (Fisher’s exact test). Frequencies of focal and broad (parentheses) SCNAs are listed. f, Mutual exclusivity analysis of focal SCNAs in SHH. g, Clinical implications of SCNAs affecting MYCN, GLI2, or PTCH1 in SHH (log-rank tests).
Figure 3
Figure 3. The genomic landscape of Group 3 and Group 4 medulloblastoma
a, b, GISTIC2 plots depicting significant SCNAs in Group 3 (a) and Group 4 (b) with subgroup-enriched regions shaded in yellow and green, respectively. c, Recurrent amplifications targeting type II (ACVR2A and ACVR2B) and type I (TGFBR1) activin receptors in Group 3. d, Recurrent SCNAs affecting the TGFβ pathway in Group 3 (P=5.73E-05, Fisher’s exact test). Frequencies of focal and broad (parentheses) SCNAs are listed. e, Enrichment plot of gene sets affected by SCNAs in Group 3 vs. Group 4.
Figure 4
Figure 4. Tandem duplication of SNCAIP defines a novel subtype of Group 4
a, Highly recurrent, focal, single copy gain of SNCAIP in Group 4. b, Paired-end mapping verifies recurrent tandem duplication of SNCAIP in Group 4. c, Schematic representation of SNCAIP tandem duplication. d, SNCAIP is a Group 4 signature gene. Upper panel. SNCAIP expression across subgroups in a published series of 103 primary medulloblastomas. Lower panel. SNCAIP ranks among the top 1% (rank=39/16,758) of highly expressed genes in Group 4. e, NMF consensus clustering of 188 expression-profiled Group 4s supports two transcriptionally distinct subtypes designated 4α and 4β (Cophenetic coefficient=0.9956). 21/22 SNCAIP duplicated cases belong to Group 4α (P=3.12E-08, Fisher’s exact test). f, SNCAIP expression is significantly elevated in Group 4α vs. 4β (P=9.31E-14, Mann-Whitney test). g, Group 4α cases harboring SNCAIP duplication exhibit a ~1.5-fold increase in SNCAIP expression.
Figure 5
Figure 5. Identification of frequent PVT1-MYC fusion genes in Group 3
a, b, RNASeq identifies multiple fusion transcripts driven by PVT1 in Group 3. Schematics depict the structures of verified PVT1-MYC (b) and PVT1-NDRG1 (c) fusion genes. c, Heatmap of the MYC/PVT1 locus showing a subset of 13 MYC-amplified Group 3 cases subsequently verified to exhibit PVT1 gene fusions (shown in d). Yellow box highlights the common breakpoint affecting the first exon/intron of PVT1, including miR-1204. d, Summary of PVT1 fusion transcripts identified in Group 3. e, f, WGS confirms complex patterns of rearrangement on chr8q24 in PVT1 fusion(+) Group 3.
Figure 6
Figure 6. Functional synergy between miR-1204 and MYC secondary to PVT1-MYC fusion
a, qRT-PCR of PVT1-encoded microRNAs confirms up-regulation of miR-1204 in PVT1-MYC fusion(+) Group 3s: MYC-balanced/fusion(−), n=4; MYC-amplified/fusion(−), n=6; MYC-amplified/fusion(+), n=8. Error bars represent standard error of the mean (SEM) and reflect variability among samples. b, c Knockdown of miR-1204 attenuates the proliferative capacity of PVT1-MYC fusion(+) MED8A medulloblastoma cells (b) but has no effect on fusion(−) ONS76 cells (c). Error bars represent the standard deviation (SD) of triplicate experiments.
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