Molecular stratification of medulloblastoma: comparison of histological and genetic methods to detect Wnt activated tumours

Neuropathol Appl Neurobiol. 2015 Feb;41(2):135-44. doi: 10.1111/nan.12161.


Aims: Wnt activation in medulloblastomas is associated with good outcome. Upfront testing and risk-adapted stratification of patients will be done in future clinical studies. In a cohort of 186 paediatric medulloblastomas our aim was to identify the optimal methods in standard clinical practice to detect this subgroup.

Methods: Nuclear accumulation of β-catenin was analysed by immunohistochemistry (IHC). DNA of FFPE tissue was amplified by PCR for single-strand conformation polymorphism analysis and direct sequencing of CTNNB1 exon 3. Copy number of chromosome 6 was analysed by multiplex ligation-dependent probe amplification and molecular inversion profiling.

Results: Different automated immunostaining systems showed similar results. Twenty-one of 186 samples had nuclear accumulation in ≥5% of cells, 17 samples showed <5% β-catenin positive nuclei. None of these 17 cases had CTNNB1 mutations, but 18 of 21 cases with ≥5% accumulation did, identifying these 18 cases as Wnt-subgroup medulloblastomas. Fifteen of 18 mutated cases showed monosomy 6, 3 had balanced chromosome 6. On the contrary, none of the CTNNB1 wild-type tumours had monosomy 6.

Conclusions: Standard neuropathological evaluation of medulloblastoma samples should include IHC of β-catenin because tumours with high nuclear accumulation of β-catenin most probably belong to the Wnt subgroup of medulloblastomas. Still, IHC alone may be insufficient to detect all Wnt cases. Similarly, chromosome 6 aberrations were not present in all CTNNB1-mutated cases. Therefore, we conclude that sequencing analysis of CTNNB1 exon 3 in combination with β-catenin IHC (possibly as pre-screening method) is a feasible and cost-efficient way for the determination of Wnt medulloblastomas.

Keywords: Wnt signalling; immunohistochemistry; medulloblastoma; mutation analysis; sequencing; β-catenin.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Cerebellar Neoplasms / genetics*
  • Child
  • Child, Preschool
  • Chromosomes, Human, Pair 6 / genetics*
  • DNA Mutational Analysis / methods*
  • Female
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Medulloblastoma / genetics*
  • Multiplex Polymerase Chain Reaction
  • Polymorphism, Single-Stranded Conformational
  • Wnt Signaling Pathway / physiology*
  • Young Adult
  • beta Catenin / genetics*


  • CTNNB1 protein, human
  • beta Catenin