Dissecting the genomic complexity underlying medulloblastoma

Authors

Jones DTW

Jäger N

Kool M

Zichner T

Hutter B

Sultan M

Cho YJ

Pugh TJ

Hovestadt V

Stütz AM

Rausch T

Pfister SM

Lichter P

Doi

10.1038/nature11284

PMID: 22832583 · DOI: 10.1038/nature11284 · Journal: Nature (2012)

TL;DR

This ICGC PedBrain study performed integrative deep-sequencing (WGS, WES, RNA-seq) of 125 pediatric medulloblastoma tumor-normal pairs across all four molecular subgroups (WNT, SHH, Group 3, Group 4). Tetraploidy was identified as a frequent early event in Group 3 and 4 tumors. Eight significantly mutated genes were found, including novel medulloblastoma drivers (DDX3X, CTDNEP1, KDM6A, TBR1). Chromatin modifiers were altered in 36% of cases, and the first medulloblastoma fusion genes were described.

Cohort & data

  • 125 medulloblastoma tumor-normal pairs from pediatric patients (age 0-17 years), collected at primary diagnosis prior to adjuvant therapy.
  • Discovery set: whole-genome sequencing (n=39) and whole-exome sequencing (n=21).
  • Replication set: custom-capture sequencing of 2,734 genes (n=65).
  • RNA sequencing: strand-specific, high-coverage in 28 cases.
  • Cancer type: MBL.
  • Dataset: mbl_icgc.
  • Methods: whole-genome-seq, whole-exome-seq, rna-seq, FISH.
  • Mean DNA coverage: 35-fold (WGS), 68-fold on-target (WES/replication).

Key findings

  • Average somatic mutation rate was 0.52/Mb (mean 10.3 non-synonymous coding SNVs per tumor in the Discovery set).
  • Positive correlation between genome-wide mutation rate and patient age (r2=0.35, p=7.8x10-5), more pronounced in diploid tumors (r2=0.52, p=3x10-5).
  • Tetraploidy was frequent in Group 3 (7/13, 54%) and Group 4 (8/20, 40%), followed by SHH (4/14, 29%) and WNT (1/7, 14%).
  • Tetraploid Group 3 and 4 tumors had significantly more large-scale copy number alterations than diploid cases (median 10 vs 4, p=0.008).
  • All four tetraploid SHH tumors harbored TP53 mutations and also displayed chromothripsis.
  • Eight genes were significantly mutated (MutSig): CTNNB1 (12%), DDX3X (8%), PTCH1 (6%), SMARCA4 (5%), KMT2D (5%), TP53 (4%), KDM6A (4%), CTDNEP1 (3%).
  • DDX3X mutations were enriched in WNT tumors (adjusted p=7.06x10-6) with clustering in the helicase domain; no truncating mutations, suggesting altered rather than lost function.
  • 45/125 cases (36%) harbored a mutation in a chromatin-modification gene (GO:0015168).
  • First medulloblastoma fusion genes identified: DNAJB6-SHH fusion in a TP53-mutant SHH tumor; LCLAT1-ERBB4 fusion; MLLT6-MRPL45 fusion.
  • TBR1 p.G275C recurrent mutation in Group 4 tumors; TBR1 and EOMES showed inverse expression correlated with DNA methylation in Group 4 subpopulations.
  • Only 48% (129/268) of non-synonymous DNA mutations were detectable at the RNA level; a further 38% resided in genes with RPKM <1.

Genes & alterations

  • CTNNB1: Mutated in 15/125 cases (12%), all in WNT subgroup (15/15 WNT tumors). Accompanied by chr6 loss in 13/15.
  • DDX3X: Mutated in 10/125 cases (8%), enriched in WNT subgroup; mutations clustered in helicase domain suggesting gain-of-function or altered activity.
  • PTCH1: Altered in 8/125 cases (6%), predominantly in SHH subgroup; frameshift indels in 6 cases, SNVs in 2.
  • SMARCA4: Mutated in 6/125 cases (5%), most frequently in Group 3 (3/26); mutations clustered in helicase domain.
  • KMT2D: Mutated in 6/125 cases (5%); recurrent indels; chromatin modifier (referred to as MLL2 in the paper).
  • TP53: Somatically mutated in 5/125 cases (4%); SHH-TP53 mutant tumors showed significantly higher mutation rates (1.1/Mb vs 0.43/Mb, p=4.5x10-6) and chromothripsis.
  • KDM6A: Truncating mutations in 5/125 cases (4%), enriched in Group 4 (4/40, 10%); H3K27 demethylase on chrX indicating tumor suppressor role.
  • CTDNEP1: Truncating alterations in 4/125 cases (3%); in 3 cases accompanied by loss of wild-type allele via isodicentric 17q; candidate 17p tumor suppressor.
  • MYCN: Amplified in 5 SHH cases.
  • SMO: Mutated in 1 SHH case (ICGC_MB12).
  • BCOR: Recurrent indels in 2 cases; chromatin modifier.
  • TBR1: p.G275C mutation in 3 Group 4 cases; T-box transcription factor involved in brain development with subgroup-specific expression.
  • EOMES: Inversely expressed with TBR1 in Group 4; methylation-dependent differential expression across subgroups.
  • ERBB4: Involved in LCLAT1-ERBB4 fusion gene; previously associated with MB oncogenesis.
  • DNAJB6: Disrupted by amplicon on chr7; first exon juxtaposed to SHH creating a fusion transcript.
  • SHH: Involved in DNAJB6-SHH fusion; extremely high expression in the fusion case vs virtually absent in 301 other MBs.

Clinical implications

  • Tetraploidy as a potential early driving event in Group 3 and 4 tumors suggests therapeutic targeting via mitotic checkpoint kinase inhibitors or kinesin inhibitors (e.g., Eg5 inhibitors) that exploit tetraploid cell vulnerability.
  • Tetraploidy may serve as a prognostic biomarker in medulloblastoma, though further validation is needed.
  • Subgroup-specific mutation patterns (e.g., DDX3X in WNT, PTCH1/MYCN in SHH, SMARCA4 in Group 3, KDM6A in Group 4) support subgroup-stratified treatment approaches.
  • CTDNEP1 as a candidate 17p tumor suppressor is relevant given the high frequency of isodicentric 17q in MB; potential therapeutic implications for Group 3 and 4 patients.
  • Chromatin modifier alterations across 36% of cases suggest epigenetic therapies as a rational avenue.

Limitations & open questions

  • All samples from primary diagnosis only; no longitudinal or recurrence data.
  • Pediatric cohort (0-17 years) limits generalizability to adult medulloblastoma.
  • Functional validation of novel driver candidates (DDX3X, CTDNEP1, TBR1) not performed in this study.
  • The role of tetraploidy as an independent prognostic marker requires prospective validation.
  • Low mutation rate and high inter-tumor heterogeneity (77% of mutated genes unique to single cases) challenge therapeutic targeting.
  • Fusion gene frequency and clinical significance require larger cohort characterization.

Citations from this paper used in the wiki

  • “Tetraploidy was most commonly observed in Group 3 (7/13, 54%) and Group 4 tumours (8/20, 40%), followed by SHH (4/14, 29%) and WNT tumours (1/7, 14%).”
  • “Only 8 genes were somatically altered in more than 3% of the whole series: CTNNB1 (15 cases, 12%); DDX3X (10 cases, 8%); PTCH1 (8 cases, 6%), SMARCA4 (6 cases, 5%), MLL2 (6 cases, 5%), TP53 (somatically mutated in 5 cases, 4%), KDM6A (5 cases, 4%) and CTDNEP1 (4 cases, 3%).”
  • “Overall, 45/125 cases (36%) harboured a mutation in a gene categorised under the Gene Ontology term ‘Chromatin Modification’.”
  • “Mutations in DDX3X were also clearly enriched in WNT tumours (adjusted p=7.06x10-6, two-tailed Fisher’s exact test with a Bonferroni correction), and these mutations were clustered within the helicase domain.”
  • “Novel classes of drugs such as mitotic checkpoint kinase or kinesin inhibitors, which target the maintenance of tetraploidy through successive cell divisions, may therefore represent a rational therapeutic strategy in these cases.”

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