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Molecular Classification

Transcriptional profiling studies of medulloblastoma tumors have shown multiple
distinct molecular subgroups with different:

  • Demographics
  • Transcriptomes
  • Somatic genetic events
  • Clinical outcomes

Classification outlined in a manuscript produced as a result of a consensus conference held in Boston 2010:


Four main subgroups of medulloblastoma identified:

1. Wnt

  • Very good long-term prognosis (over 90% long-term survival)
  • Accounts for less than 10% of medulloblastomas in children
  • Often develop in a central location abutting the brainstem
  • Occurs in older patients (median age 10yrs)
  • Wnt signalling pathway aberration is related to Beta catenin mutations leading to increased protein synthesis and cell cycling
  • Germ line mutations of the Wnt pathway inhibitor APC predispose to Turcot syndrome (associated with increased risk of medulloblastoma)
  • Very likely to be an etiological role for canonical Wnt signaling in
    the pathogenesis of these tumors
  • Almost all have classic histology
  • Tends to occur in older children
  • CTNNB1 mutations common
  • Nuclear immunohistochemical staining for b-catenin common
  • Monosomy six (deletion of one copy of chromosome 6 in the tumor) common

2. Shh (Sonic Hedgehog subgroup)

  • Sonic Hedgehog pathway is secondary to a PTCH mutation
  • Accounts for about 25% of cases
  • Sonic Hedgehog signaling pathway is thought to drive tumor development in these cases:
    • Gorlin syndrome = Individuals with germ line mutations in the Shh receptor PTCH and this syndrome predisposes to the development of medulloblastoma
    • Germ line mutations of the Shh inhibitor SUFU also predispose to the development of medulloblastoma (especially infantile medulloblastoma)
  • Shh tumors identified on the basis of transcriptional profiling
  • Shh subgroup tumors have high levels of expression of MYCN
  • Deletion of chromosome 9q apparently limited to Shh medulloblastomas (PTCH gene is located at chromosome 9q22)
  • Frequent in infants and adults over 16 years of age, but less frequent in children
  • The great majority of nodular/desmoplastic medulloblastomas belong to the Shh subgroup
  • Frequently arise in the cerebellar hemisphere
  • Prognosis of Shh medulloblastoma similar to Group 4 medulloblastomas (moderately good)

3. Group 3

  • Mostly classic medulloblastoma histological picture
  • Accounts for 25% of medulloblastoma
  • High incidence of large cell/anaplastic histology
  • Frequently have metastatic disease at diagnosis
  • Poor prognosis
  • Immunohistochemical positivity for NPR3
  • Transcriptional profile that clusters with other Group 3 tumors
  • Group 3 and Wnt subgroup tumors have high levels of expression of MYC
  • Group 3 can be further subdivided into:
    • Group 3 alpha:
      • All patients with MYC amplifications and group 3 diagnosis
      • high risk of recurrence and death
    • Group 3 beta:
      • No MYC amplifications
      • Better prognosis with clinical outcome similar to Group 4 patients
  • Amplification and over-expression of the medulloblastoma oncogene OTX2 appears to be restricted to Group 3 and Group 4 tumors
  • Group 3 tumors are much more likely than Group 4 tumors to show
    gain of chromosome 1q, and/or loss of chromosome 5q and chromosome 10q

4. Group 4

  • Prototype for medulloblastoma: classic histology medulloblastoma with isochromosome 17q in a 6 - 8 year old boy
  • Molecular pathogenesis of Group 4 tumors unclear
  • Transcriptional profile that clusters with other Group 4 medulloblastomas
  • KCNA1 suggested as an immunohistochemical marker for Group 4 tumors (requires validation)
  • Isochromosome 17q is also seen in Group 3 tumors (26%), but is much more common in Group 4 tumors where it is the most common cytogenetic change observed (66%)
  • Tumors in 80% of females with group 4 medulloblastoma show loss of the X chromosome

Comparison of the various subgroups of medulloblastoma taken from consensus paper:

These findings need to be validated prospectively and as time goes on this classification will be refined.




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