DKFZ / ICGC PedBrain Medulloblastoma WGS 2017 (Northcott et al.)

Overview

The DKFZ / ICGC PedBrain medulloblastoma cohort is the largest integrated genomic and epigenomic survey of medulloblastoma assembled to date, generated by the ICGC PedBrain Tumour and MAGIC consortia. Northcott et al. profiled 491 diagnostic tumor-normal pairs by whole-genome sequencing and 1,256 additional cases by Illumina 450K methylation array, spanning all four consensus subgroups (WNT, SHH, Group 3, Group 4). The study doubled the proportion of explained Group 3 and Group 4 cases by nominating new subgroup-specific driver events, including hotspot Kelch-domain insertions in KBTBD4 and an “enhancer-hijacking” mechanism activating PRDM6 via SNCAIP tandem duplications in Group 4 PMID:28726821.

Composition

• Sequencing cohort: 491 diagnostic medulloblastoma tumor-normal pairs after QC/de-duplication (579 enrolled); ages 1 month to 50 years (median 8 years).
• Sequencing breakdown: whole genomes n=390 (190 previously published in PMID:22832583, PMID:22832587, PMID:22722829; 200 unpublished); whole exomes n=101 (from PCGP/MAGIC prior studies).
• Methylation profiling: 1,256 cases on Illumina 450K arrays (including 396/491 [80.7%] of the NGS cohort).
• Transcriptomes: RNA-seq n=164; Affymetrix expression arrays n=392.
• ChIP-seq: H3K27ac and CTCF on n=28 subset for enhancer mapping.
• Cancer type: MBL PMID:28726821.

Assays / panels (linked)

• whole-genome-seq
• whole-exome-seq
• rna-seq
• 450k-methylation-array
• chip-seq
• mutational-signatures
• tsne
• mutsig
• genome-music

Papers using this cohort

• PMID:28726821 — Northcott et al. 2017; integrated WGS and methylation survey of 491 MBs defining new subgroup drivers and eight methylation subtypes within Group 3/4.

Notable findings derived from this cohort

• Driver events confidently assigned to 76% of Group 3 (n=131) and 82% of Group 4 (n=193) cases — more than doubling the previously explained fraction relative to prior series of ~173 WGS tumors PMID:28726821.
• KBTBD4 hotspot in-frame insertions (residues 308–313 of the Kelch domain) are the most prevalent driver in methylation subtypes II (21%) and VII (14%); Group 3 predominant insertion R313delinsPRR, Group 4 predominant P311delinsPP PMID:28726821.
• Enhancer-hijacking by SNCAIP tandem duplications activates PRDM6 (≥20-fold upregulation, P=6.07×10⁻²⁴) as the most prevalent driver in Group 4 (17% of n=193) PMID:28726821.
• t-SNE on 12,454 most-variable methylation probes across 740 Group 3/4 cases resolves eight molecular subtypes (I–VIII), each with distinctive driver-event enrichment; subtype structure stabilizes at ≥500 samples PMID:28726821.
• All 36 WNT tumors sequenced carried at least one driver; 86% had somatic CTNNB1 hotspot mutations; 3 CTNNB1-wild-type WNT MBs carried pathogenic germline APC variants (Turcot syndrome) PMID:28726821.
• 24 mutational signatures detected; Signature 3 (BRCA1/2-associated) unexpectedly common in Group 3 and Group 4; Signature 18 enriched in Group 3 (P=4.7×10⁻⁵); Signature 5 in Group 4 (P=1.0×10⁻¹¹, age-correlated) PMID:28726821.
• HAT-complex genes (CREBBP, KAT6B, EP300, BRPF1, KANSL1) recurrently mutated in 19% of SHH MBs, providing rationale for HAT-pathway epigenetic therapy PMID:28726821.
• Six IDH1 R132C mutations identified (5 SHH, 1 WNT); IDH1-mutant SHH tumors are CIMP+, paralleling IDH-mutant glioma PMID:28726821.

Sources

• Northcott PA, Buchhalter I, Morrissy AS, et al. The whole-genome landscape of medulloblastoma subtypes. Nature. 2017;547(7663):311-317. PMID:28726821

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