Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations

Nature. 2012 Aug 2;488(7409):106-10. doi: 10.1038/nature11329.

Abstract

Medulloblastomas are the most common malignant brain tumours in children. Identifying and understanding the genetic events that drive these tumours is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma on the basis of transcriptional and copy number profiles. Here we use whole-exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas have low mutation rates consistent with other paediatric tumours, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were newly identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR and LDB1. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant, but not wild-type, β-catenin. Together, our study reveals the alteration of WNT, hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic β-catenin signalling in medulloblastoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cerebellar Neoplasms / classification
  • Cerebellar Neoplasms / genetics*
  • Child
  • DEAD-box RNA Helicases / chemistry
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism
  • DNA Helicases / chemistry
  • DNA Helicases / genetics
  • DNA-Binding Proteins / genetics
  • Exome / genetics*
  • Genome, Human / genetics*
  • Hedgehog Proteins / metabolism
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • LIM Domain Proteins / genetics
  • Medulloblastoma / classification
  • Medulloblastoma / genetics*
  • Models, Molecular
  • Mutation / genetics*
  • Neoplasm Proteins / genetics
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics
  • Patched Receptors
  • Patched-1 Receptor
  • Promoter Regions, Genetic / genetics
  • Protein Structure, Tertiary / genetics
  • Proto-Oncogene Proteins / genetics
  • Receptors, Cell Surface / genetics
  • Repressor Proteins / genetics
  • Signal Transduction
  • TCF Transcription Factors / metabolism
  • Transcription Factors / chemistry
  • Transcription Factors / genetics
  • Tumor Suppressor Protein p53 / genetics
  • Wnt Proteins / metabolism
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • BCOR protein, human
  • CTNNB1 protein, human
  • DNA-Binding Proteins
  • GPS2 protein, human
  • Hedgehog Proteins
  • Intracellular Signaling Peptides and Proteins
  • KMT2D protein, human
  • LDB1 protein, human
  • LIM Domain Proteins
  • Neoplasm Proteins
  • Nuclear Proteins
  • PTCH protein, human
  • Patched Receptors
  • Patched-1 Receptor
  • Proto-Oncogene Proteins
  • Receptors, Cell Surface
  • Repressor Proteins
  • SHH protein, human
  • TCF Transcription Factors
  • TP53 protein, human
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Wnt Proteins
  • beta Catenin
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase
  • DDX3X protein, human
  • SMARCA4 protein, human
  • DNA Helicases
  • DEAD-box RNA Helicases