Medulloblastoma — SickKids 2016

Overview

Whole-genome sequencing of 33 patient-matched primary/recurrence medulloblastoma (MBL) pairs (46 total human samples) from a multi-institutional pediatric brain tumor cohort, combined with whole-exome sequencing of 3 FFPE pairs. The study was designed to characterize clonal evolution between diagnosis and relapse. Raw sequencing deposited at EGA (EGAD00001000946). Reference genome GRCh37/hg19.

Composition

  • 15 matched primary + recurrent pairs with germline controls: whole-genome-seq.
  • 18 matched primary + recurrent pairs without germline: whole-genome-seq.
  • 10 recurrence-only samples with germline: whole-genome-seq.
  • 3 FFPE matched pairs: whole-exome-seq (Nextera Rapid Capture).
  • Total human samples: 46 from 33 patients.
  • All four medulloblastoma molecular subgroups represented (Shh, Wnt, Group 3, Group 4).
  • Cancer type: MBL (medulloblastoma).

Assays / panels (linked)

Papers using this cohort

  • PMID:26760213 — Morrissy et al. 2016, “Divergent clonal selection dominates medulloblastoma at recurrence,” Nature.

Notable findings derived from this cohort

  • On average only 11.8% of somatic SNVs/indels are shared between matched diagnostic and recurrent tumors, demonstrating massive clonal divergence at relapse PMID:26760213.
  • Somatic mutational burden increases ~5-fold post-therapy in 13/15 patient pairs (P = 2.7 × 10⁻⁴); structural-variant burden also rises PMID:26760213.
  • Recurrence arises from pre-existing minor subclones (<5% at diagnosis) confirmed in 16/20 patients by ultra-deep targeted resequencing PMID:26760213.
  • TP53-pathway alterations (including TP53 mutations) and DYNC1H1/chr14q deficits together affect 79% of recurrent Shh medulloblastoma PMID:26760213.
  • Drug-actionable targets at recurrence differ from those at diagnosis in the majority of patients (5/9 with any actionable alteration); 2/9 had a complete actionable-target switch PMID:26760213.
  • Branched clonal evolution demonstrated in all 14 germline-matched cases; Group 4 tumors significantly more heterogeneous at recurrence (Shannon Index, P = 0.029) PMID:26760213.

Sources

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