Wnt/Wingless pathway activation and chromosome 6 loss characterize a distinct molecular sub-group of medulloblastomas associated with a favorable prognosis

Cell Cycle. 2006 Nov;5(22):2666-70. doi: 10.4161/cc.5.22.3446. Epub 2006 Nov 15.


The accurate assessment of disease risk remains a major goal in children with medulloblastoma. Activation of the canonical Wnt/Wingless (Wnt/Wg) signalling pathway occurs in up to 25% of cases and is associated with a favorable disease outcome. To explore the molecular pathogenesis of Wnt/Wg-active medulloblastomas, and to investigate any genetic basis for their observed clinical behavior, we assessed a series of primary medulloblastomas for evidence of Wnt/Wg pathway activation, alongside a genome-wide analysis of associated copy-number aberrations. Cases displaying evidence of Wnt/Wg activation (CTNNB1 mutation and/or beta-catenin nuclear stabilisation) were exclusively associated with a distinct genomic signature involving loss of an entire copy of chromosome 6 but few other aberrations (p < 0.001). In contrast, Wnt/Wg-negative tumors coclustered into an unrelated sub-group characterised by multiple established genomic defects common in medulloblastoma (losses of chromosomes 17p, 8, 10 and 16; gains of chromosomes 7 and 17q). Further investigation of specific genetic defects in a larger independent cohort demonstrated that loss of chromosome 6 was exclusively observed in Wnt/Wg-active tumors, but not in Wnt/Wg-negative cases (8/13 vs. 0/19; p = 0.0001), while pathway activation was independent of chromosome 17 aberrations, the most common chromosomal alterations detected in medulloblastoma (p = 0.005). Wnt/Wg-active tumors could not be distinguished on the basis of clinical or pathological disease features. Our data indicate that Wnt/Wg-active tumors represent an independent molecular sub-group of medulloblastomas characterised by a distinct pattern of genomic aberrations. These findings provide a strong biological basis to support (1) the idiosyncratic clinical behavior of Wnt/Wg-active medulloblastomas, and (2) the development of beta-catenin status as an independent marker for therapeutic stratification in this disease.

Publication types

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

MeSH terms

  • Adolescent
  • Cerebellar Neoplasms / classification*
  • Cerebellar Neoplasms / diagnosis*
  • Cerebellar Neoplasms / genetics
  • Child
  • Child, Preschool
  • Chromosome Deletion*
  • Chromosomes, Human, Pair 6*
  • Cohort Studies
  • Female
  • Humans
  • Infant
  • Male
  • Medulloblastoma / classification*
  • Medulloblastoma / diagnosis*
  • Medulloblastoma / genetics
  • Prognosis
  • Signal Transduction
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism*
  • beta Catenin / genetics
  • beta Catenin / metabolism


  • Wnt Proteins
  • beta Catenin