Medulloblastoma (ICGC, Nature 2012)

Overview

The ICGC PedBrain medulloblastoma dataset comprises 125 matched pediatric medulloblastoma tumor/normal pairs from children aged 0-17 years, collected at primary diagnosis prior to adjuvant therapy (Jones et al., Nature 2012). The cohort uses an integrative design combining whole-genome sequencing, whole-exome sequencing, RNA-seq, and FISH. It spans all four molecular subgroups (WNT, SHH, Group 3, Group 4) and was the first study to describe medulloblastoma fusion genes and to identify tetraploidy as a frequent early event in Group 3 and 4 tumors.

Composition

  • 125 pediatric medulloblastoma tumor/normal pairs (age 0-17 years)
  • Cancer type: MBL
  • Molecular subgroups represented: WNT (n=15), SHH (n=30+), Group 3, Group 4
  • Discovery set: WGS (n=39) + WES (n=21)
  • Replication set: custom-capture sequencing of 2,734 genes (n=65)
  • RNA sequencing: 28 cases
  • Average somatic mutation rate: 0.52/Mb (mean 10.3 non-synonymous coding SNVs per tumor)

Assays / panels (linked)

  • whole-genome-seq — 39 discovery cases; 35-fold mean DNA coverage
  • whole-exome-seq — 21 discovery cases; 68-fold on-target mean coverage
  • rna-seq — strand-specific, high-coverage; 28 cases
  • fish — validation of copy-number alterations and structural rearrangements

Papers using this cohort

Notable findings derived from this cohort

  • 8 significantly mutated genes (MutSig): CTNNB1 (12%), DDX3X (8%), PTCH1 (6%), SMARCA4 (5%), KMT2D (5%), TP53 (4%), KDM6A (4%), CTDNEP1 (3%) PMID:22832583
  • Tetraploidy identified in 54% of Group 3 and 40% of Group 4 tumors; associated with significantly more large-scale copy-number alterations PMID:22832583
  • First medulloblastoma fusion genes described: DNAJB6-SHH, LCLAT1-ERBB4, MLLT6-MRPL45 PMID:22832583
  • 36% of cases (45/125) harbored a chromatin-modification gene mutation PMID:22832583
  • Only 48% of non-synonymous DNA mutations detectable at RNA level; further 38% in genes with RPKM <1 PMID:22832583
  • Positive correlation between genome-wide mutation rate and patient age (r2=0.35, p=7.8e-5) PMID:22832583

Sources

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