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Dissecting the Genomic Complexity Underlying Medulloblastoma

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Dissecting the Genomic Complexity Underlying Medulloblastoma LETTER doi:10.1038/nature11284 Dissecting the genomic complexity underlying medulloblastoma A list of authors and their affiliations appears at the end of the paper Medulloblastoma is an aggressively growing tumour, arising in Some cases probably went through even higher polyploidy states the cerebellum or medulla/brain stem. It is the most common before reaching an approximately 4n baseline (for example malignant brain tumour in children, and shows tremendous bio- ICGC_MB45, displaying 4n chromosomes with 4:0 or 3:1 allele ratios; logical and clinical heterogeneity1. Despite recent treatment Supplementary Fig. 2). Across the discovery set, tetraploidy was most advances, approximately 40% of children experience tumour commonly observed in Group 3 (7 out of 13, 54%) and Group 4 recurrence, and 30% will die from their disease. Those who survive tumours (8 out of 20, 40%), followed by SHH (4 out of 14, 29%) and often have a significantly reduced quality of life. Four tumour WNT tumours (1 out of 7, 14%). Interestingly, the four tetraploid SHH subgroups with distinct clinical, biological and genetic profiles tumours all harboured TP53 mutations and also displayed chromo- are currently identified2,3. WNT tumours, showing activated thripsis6. Tetraploid Group 3 and 4 tumours showed significantly wingless pathway signalling, carry a favourable prognosis under more large-scale copy number alterations compared with diploid cases current treatment regimens4. SHH tumours show hedgehog (median 10 changes per tumour in tetraploid versus 4 per tumour in pathway activation, and have an intermediate prognosis2. Group 3 diploid cases, P 5 0.008, two-tailed Mann–Whitney U-test; Supplemen- and 4 tumours are molecularly less well characterized, and also tary Fig. 3). Thus, tetraploidy followed by genomic instability may be present the greatest clinical challenges2,3,5. The full repertoire of an early driving event in a large proportion of Group 3 and 4 medullo- genetic events driving this distinction, however, remains unclear. blastomas, which pose a significant clinical challenge due to their Here we describe an integrative deep-sequencing analysis of 125 dismal prognosis and lack of targeted treatment options. Novel classes tumour–normal pairs, conducted as part of the International of drugs such as mitotic checkpoint kinase or kinesin inhibitors, which Cancer Genome Consortium (ICGC) PedBrain Tumor Project. target the maintenance of tetraploidy through successive cell divisions, Tetraploidy was identified as a frequent early event in Group 3 may therefore represent a rational therapeutic strategy in these and 4 tumours, and a positive correlation between patient age cases7,8. The value of tetraploidy as a prognostic marker also requires and mutation rate was observed. Several recurrent mutations further investigation. were identified, both in known medulloblastoma-related genes The average somatic mutation rate in the WGS cohort was 0.52 per (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously megabase (Mb), with an average of 10.3 non-synonymous coding linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), single-nucleotide variants (SNVs) in the discovery cohort (Supplemen- often in subgroup-specific patterns. RNA sequencing confirmed tary Table 2). This is slightly higher than previously reported for these alterations, and revealed the expression of what are, to our medulloblastoma9, possibly due to improved coverage and technical knowledge, the first medulloblastoma fusion genes identified. sensitivity, but considerably lower than in deep-sequenced adult Chromatin modifiers were frequently altered across all subgroups. tumours, for example10,11. There were significantly fewer transitions These findings enhance our understanding of the genomic in the somatic alterations compared with germline variation complexity and heterogeneity underlying medulloblastoma, and (P 5 4.6 3 1027, Wilcoxon rank-sum test; Supplementary Fig. 4). All provide several potential targets for new therapeutics, especially coding somatic SNVs identified in the combined cohort are listed in for Group 3 and 4 patients. Supplementary Table 3. As a first phase of the International Cancer Genome Consortium We identified a positive correlation between genome-wide mutation (ICGC) PedBrain Tumor Project (http://www.pedbraintumor.org), rate and patient age, as previously reported for coding mutations9 we have collected matched tumour and germline samples from 125 (r2 5 0.35, P 5 7.8 3 1025 Pearson’s product–moment correlation; medulloblastoma patients aged from 0 to 17 years (Supplementary Fig. 1c). Intriguingly, this association was more pronounced in diploid Table 1). Whole-genome sequencing (WGS, n 5 39) and whole-exome tumours (r2 5 0.52, P 5 3 3 1025), and virtually absent in tetraploid sequencing (WES, n 5 21) were applied to a ‘discovery’ set, with a cases (r2 5 0.04, P 5 0.5) (Supplementary Fig. 5a, b). A similar trend custom-capture approach used to sequence 2,734 genes in an additional was observed for non-synonymous mutations across the discovery ‘replication’ set (n 5 65). All tumour samples were obtained at primary cohort (Supplementary Fig. 5c). Coverage level did not correlate with diagnosis, before adjuvant therapy, and the distribution of molecular mutation rate (Supplementary Fig. 5d). One explanation may be that subgroups was similar across cohorts (Supplementary Fig. 1). all medulloblastomas originate during embryogenesis, with some Investigation of genome-wide somatic mutation allele frequencies tumours needing to accumulate more genetic ‘hits’ before becoming identified several cases with a clear peak at approximately 25%, rather symptomatic. Alternatively, tumours arising in older patients may than the expected approximately 50% allele frequency for early, derive from more differentiated cells that require a greater number heterozygous events (Fig. 1a). Analysis of coverage depth and allele of alterations to undergo malignant transformation. Investigation of frequencies in regions of copy-number change ruled out stromal con- additional tumours from older patients may help to clarify this. tamination, but rather indicated a tetraploid baseline in the tumour Five SHH tumours harbouring TP53 mutations, including three genome (Fig. 1b). Predicted ploidy status was confirmed by fluor- previously described Li–Fraumeni syndrome (LFS)-associated tumours escence in situ hybridization (FISH) using multiple centromeric with germline mutations6, one newly identified LFS case (ICGC_MB23), probes in 17 out of 18 cases analysed (Fig. 1a). The extremely low and one somatically mutated tumour (ICGC_MB34), had significantly fraction of mutations at approximately 50% allele frequency indicates more mutations than the remaining cases, both genome wide (mean 1.1 that genome duplication occurred very early during tumorigenesis. per Mb versus 0.43 per Mb, P 5 4.5 3 1026; two-tailed t-test) and for 100 | NATURE | VOL 488 | 2 AUGUST 2012 ©2012 Macmillan Publishers Limited. All rights reserved LETTER RESEARCH a Diploid Tetraploid c ICGC_MB1 50% ICGC_MB37 (diploid) 25% ICGC_MB15 (tetraploid) ICGC_MB16 WNT ICGC_MB18 SHH ICGC_MB31 ICGC_MB35 SHH-p53 ICGC_MB37 Grp3 ICGC_MB49 Grp4 ICGC_MB5 ICGC_MB6 Density Density ICGC_MB7 ICGC_MB15 ICGC_MB17 R2 = 0.35 ICGC_MB26 ICGC_MB34 Somatic SNVs genome-wide 500 1,500 2,500 3,500 4,500 01234 012345 0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0 1234567891011121314151617 Mutant allele frequency Mutant allele frequency Age at diagnosis (years) b 2.0 ICGC_MB15 0.5 d P = 0.001 P = 0.017 P = 0.004 1.5 0.4 2:2 4:3 1.0 3:2 versus control 0.5 0.3 2:1 Coverage ratio tumour 0.0 0.5 Tumour BAF 0.2 0.4 0.3 0.1 Somatic SNVs genomewide 1,000 2,000 3,000 4,000 0.2 AXY 3:0 Tumour BAF 0.1 0.0 P = 0.017 P = 0.008 P = 0.013 0.0 WNT SHH SHH-p53 Grp3 Grp4 0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00 1234567891011121416182022XY Coverage ratio tumour versus control Subgroup Chromosome Figure 1 | Tetraploidy is a frequent early event in medulloblastoma which are heterozygous in the germ line. Right, genome alteration print (GAP) tumorigenesis, and mutation rates vary with age and subgroup. of segmented copy number and allele frequency profiles. Chromosomes with a, Distributions of genome-wide somatic mutation allele frequencies (the predicted 3:0/2:1/3:2 allele ratios show a BAF of approximately 0/0.33/0.4 and proportion of sequence reads supporting a mutation) for diploid tumours (with coverage ratios of approximately 0.75/0.75/1.25. Owing to random sampling, a peak at ,50% for heterozygous events, n 5 7) and tetraploid cases (with a the 2:2 allele ratio is slightly below 0.5. c, Genome-wide somatic mutation rates peak at ,25%, n 5 7). Insets show centromeric FISH for chromosomes 1 (red) are positively correlated with patient age (n 5 39). Grp, Group. d, Distribution and 11 (green), confirming the predicted ploidy status. b, Top left, rescaled of somatic mutation rates by tumour subgroup (n 5 39). P values are according tumour:germline coverage ratio, indicating copy-number gains (red) or losses to a Wilcoxon rank-sum test with Bonferroni correction. SHH-p53, SHH- (green). Bottom left, B-allele frequency (BAF) in the tumour at SNP positions subgroup tumours harbouring a somatic or germline TP53 mutation. non-synonymous changes (mean 23 versus 8.8, P 5 2.6 3 1026). mutated in 5 cases, 4%), KDM6A (5 cases, 4%) and CTDNEP1 (4 cases, Interestingly, the WNT subgroup, which typically shows a good pro- 3%) (Fig. 2). These were also the only genes found to be significantly gnosis and few copy-number changes, had the next highest mutation altered upon analysis of the combined cohort with MutSig, an algo- rate (Fig. 1d). rithm testing whether the observed mutations in a gene are not simply Forty-one somatic, coding, small insertions/deletions (Indels) were a consequence of random background mutation processes.
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