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. 2012 Aug 2;488(7409):100-5.
doi: 10.1038/nature11284.

Dissecting the genomic complexity underlying medulloblastoma

David T W Jones  1 , Natalie Jäger, Marcel Kool, Thomas Zichner, Barbara Hutter, Marc Sultan, Yoon-Jae Cho, Trevor J Pugh, Volker Hovestadt, Adrian M Stütz, Tobias Rausch, Hans-Jörg Warnatz, Marina Ryzhova, Sebastian Bender, Dominik Sturm, Sabrina Pleier, Huriye Cin, Elke Pfaff, Laura Sieber, Andrea Wittmann, Marc Remke, Hendrik Witt, Sonja Hutter, Theophilos Tzaridis, Joachim Weischenfeldt, Benjamin Raeder, Meryem Avci, Vyacheslav Amstislavskiy, Marc Zapatka, Ursula D Weber, Qi Wang, Bärbel Lasitschka, Cynthia C Bartholomae, Manfred Schmidt, Christof von Kalle, Volker Ast, Chris Lawerenz, Jürgen Eils, Rolf Kabbe, Vladimir Benes, Peter van Sluis, Jan Koster, Richard Volckmann, David Shih, Matthew J Betts, Robert B Russell, Simona Coco, Gian Paolo Tonini, Ulrich Schüller, Volkmar Hans, Norbert Graf, Yoo-Jin Kim, Camelia Monoranu, Wolfgang Roggendorf, Andreas Unterberg, Christel Herold-Mende, Till Milde, Andreas E Kulozik, Andreas von Deimling, Olaf Witt, Eberhard Maass, Jochen Rössler, Martin Ebinger, Martin U Schuhmann, Michael C Frühwald, Martin Hasselblatt, Nada Jabado, Stefan Rutkowski, André O von Bueren, Dan Williamson, Steven C Clifford, Martin G McCabe, V Peter Collins, Stephan Wolf, Stefan Wiemann, Hans Lehrach, Benedikt Brors, Wolfram Scheurlen, Jörg Felsberg, Guido Reifenberger, Paul A Northcott, Michael D Taylor, Matthew Meyerson, Scott L Pomeroy, Marie-Laure Yaspo, Jan O Korbel, Andrey Korshunov, Roland Eils, Stefan M Pfister, Peter Lichter
Affiliations

Dissecting the genomic complexity underlying medulloblastoma

David T W Jones et al. Nature. .

Abstract

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. 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. WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis. Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges. 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 linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA sequencing confirmed these alterations, and revealed the expression of what are, to our knowledge, the first medulloblastoma fusion genes identified. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 and 4 patients.

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Figures

Figure 1
Figure 1. Tetraploidy is a frequent early event in MB tumourigenesis, and mutation rates vary with age and subgroup
a, Distributions of genome-wide somatic mutation allele frequencies (the proportion of sequence reads supporting a mutation) for diploid tumours (with a peak at ~50% for heterozygous events, n=7) and tetraploid cases (with a peak at ~25%, n=7). Insets show centromeric FISH for chromosomes 1 (red) and 11 (green), confirming the predicted ploidy status. b, Top left: Rescaled tumour:germline coverage ratio, indicating copy-number gains (red) or losses (green). Bottom left: B-Allele frequency (BAF) in the tumour at SNP positions which are heterozygous in the germline. Right: Genome alteration print (GAP) of segmented copy number and allele frequency profiles. Chromosomes with predicted 3:0/2:1/3:2 allele ratios show a BAF of ~0/0.33/0.4 and coverage ratios of ~0.75/0.75/1.25. Due to random sampling, the 2:2 allele ratio is slightly below 0.5. c, Genome-wide somatic mutation rates are positively correlated with patient age (n=39). d, Distribution of somatic mutation rates by tumour subgroup (n=39). p-values are according to a Wilcoxon rank-sum test with Bonferroni correction. SHH-p53: SHH-subgroup tumours harbouring a somatic or germline TP53 mutation.
Figure 2
Figure 2. Subgroup specificity of common genetic alterations
Summary of clinical data and recurrent alterations in the combined cohort (n=125). Genes which were found to be significantly mutated by MutSig analysis were included. UPD: uniparental disomy, ND: no material available for conclusive molecular subgroup assignment.
Figure 3
Figure 3. Identification of novel fusion genes in MB
a, Read-depth plot with log2 tumour:germline coverage ratio showing alterations on chromosome 7 in ICGC_MB34. Lines indicate connected segments. b, Schematic of the rearrangement. c, Details of the SHH fusion gene structure and support for its expression, derived from RNA sequencing data.
Figure 4
Figure 4. Integration of mutation, expression and methylation data shows differential regulation of TBR1 and EOMES in medulloblastoma
a, Microarray data showing clear differences in TBR1 and EOMES expression between medulloblastoma subgroups (n=301). b, DNA methylation of TBR1 (n=54), ranging from low (blue) to high (red). Horizontal red bar indicates the region used for correlation analysis in c. c, Expression of TBR1 is tightly correlated with gene methylation (n=54; Pearson’s correlation values, r). SHH tumours show high methylation and virtually no expression, while WNT, Group 3 and Group 4 tumours display a more varied pattern. d, Expression levels of TBR1 (diamonds) and EOMES (circles) are inversely related in Group 4 tumours (n=104).
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