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Tuesday 2 March 2004

Definition: Medulloblastoma is a highly malignant embryonal tumor of the cerebellum that accounts for 20%-25% of all intracranial pediatric tumors. Medulloblastoma is the most frequent malignant paediatric brain tumour.


- Medulloblastoma

The most common malignant brain tumor in children is medulloblastoma, the prototype PNET. Primitive neuroectodermal tumors that arise in the cerebellum are generally classified as medulloblastoma, whereas similar histologic entities that arise in other locations are referred to

The molecular classification by Kool et al. (2008, 18769486)

Five molecular subtypes were identified (18769486), characterized by
- WNT signaling (A)
- SHH signaling (B)
- expression of neuronal differentiation genes (C and D) or photoreceptor genes (D and E).

Mutations in beta-catenin were identified in all 9 type A tumors, but not in any other tumor. PTCH1 mutations were exclusively identified in type B tumors.

CGH analysis identified several fully or partly subtype-specific chromosomal aberrations.

Monosomy of chromosome 6 occurred only in type A tumors, loss of 9q mostly occurred in type B tumors, whereas chromosome 17 aberrations, most common in medulloblastoma, were strongly associated with type C or D tumors.

Loss of the inactivated X-chromosome was highly specific for female cases of type C, D and E tumors.

Gene expression levels faithfully reflected the chromosomal copy number changes.

Clinicopathological features significantly different between the 5 subtypes included metastatic disease and age at diagnosis and histology.

Metastatic disease at diagnosis was significantly associated with subtypes C and D and most strongly with subtype E. Patients below 3 yrs of age had type B, D, or E tumors. Type B included most desmoplastic cases.

WNT-activated medulloblastoma

Patients with WNT-activated medulloblastoma have a favorable prognosis, suggesting that these patients could be treated less intensively, thereby reducing the side-effects.


The most frequent chromosomal rearrangement in medulloblastoma is isochromosome 17, or i(17q).

- 17p deletion (TP53, KCTD11)

  • isochromosome 17q - i(17q) (16419060)
  • Molecular biology

- somatic mutations in PTCH and PTCH2 genes
- allelotyping
- expression profiling: 14500378
- The activation of the Wnt/beta-catenin pathway occurs in 10-15% of medulloblastomas and has been recently described as a marker for favourable patient outcome. CTNNB1-mutated tumours represent a distinct molecular subgroup of medulloblastomas with favourable outcome. (19197950)


- Losses

- Gains


- 2p amplification (MYCN, DDX1)
- MYC by 8q24 amplification (16%) (16320246)
- 10p11 amplification (16320246)
- 3q amplification (16320246)

Allelotyping (11857089)

Region LOH% Genes
1p32 - PTCH2
5q22 - APC
7q 58.3%
8p22-23.1 66.7% -
9q22.3 - PTCH1
16q 58.3%
17p13.1-p12 58.3% TP53
17q 66.7%

Gene inactivating mutations

PTCH2 1p32 MIM.603673
APC 5q21-5q22 MIM.175100
SUFU 10q24-q25 MIM.607035
BRCA2 13q12.3 MIM.600185

Gene activating mutations

CTNNB1 3p22-p21.3 MIM.116806

Differential diagnosis

- atypical teratoid/rhabdoid tumor (ATRT)


- Fanconi anemia (Fanconi syndrome)

  • +/- BRCA2 biallelic mutations (14670928)

See also

- MYC-driben medulloblastoma


- Ferretti E, Smaele ED, Marcotullio LD, Screpanti I, Gulino A. Hedgehog checkpoints in medulloblastoma: the chromosome 17p deletion paradigm. Trends Mol Med. 2005 Dec;11(12):537-45. PMID: 16290230


- The clinical implications of medulloblastoma subgroups. Northcott PA, Korshunov A, Pfister SM, Taylor MD. Nat Rev Neurol. 2012 May 8. PMID: 22565209

- Global gene expression profiling confirms the molecular fidelity of primary tumor-based orthotopic xenograft mouse models of medulloblastoma. Zhao X, Liu Z, Yu L, Zhang Y, Baxter P, Voicu H, Gurusiddappa S, Luan J, Su JM, Leung HC, Li XN. Neuro Oncol. 2012 May;14(5):574-83. PMID: 22459127

- Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. Kool M, Koster J, Bunt J, Hasselt NE, Lakeman A, van Sluis P, Troost D, Meeteren NS, Caron HN, Cloos J, Mrsić A, Ylstra B, Grajkowska W, Hartmann W, Pietsch T, Ellison D, Clifford SC, Versteeg R. PLoS One. 2008 Aug 28;3(8):e3088. PMID: 18769486 (Free)

- Subgroup-specific alternative splicing in medulloblastoma. Dubuc AM, Morrissy AS, Kloosterhof NK, Northcott PA, Yu EP, Shih D, Peacock J, Grajkowska W, van Meter T, Eberhart CG, Pfister S, Marra MA, Weiss WA, Scherer SW, Rutka JT, French PJ, Taylor MD. Acta Neuropathol. 2012 Apr;123(4):485-99. PMID: 22358458 (Free)

- Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas. Kool M, Korshunov A, Remke M, Jones DT, Schlanstein M, Northcott PA, Cho YJ, Koster J, Schouten-van Meeteren A, van Vuurden D, Clifford SC, Pietsch T, von Bueren AO, Rutkowski S, McCabe M, Collins VP, Bäcklund ML, Haberler C, Bourdeaut F, Delattre O, Doz F, Ellison DW, Gilbertson RJ, Pomeroy SL, Taylor MD, Lichter P, Pfister SM. Acta Neuropathol. 2012 Apr;123(4):473-84. PMID: 22358457 [Free]

- Beta-catenin status in paediatric medulloblastomas: correlation of immunohistochemical expression with mutational status, genetic profiles, and clinical characteristics. Fattet S, Haberler C, Legoix P, Varlet P, Lellouch-Tubiana A, Lair S, Manie E, Raquin MA, Bours D, Carpentier S, Barillot E, Grill J, Doz F, Puget S, Janoueix-Lerosey I, Delattre O. J Pathol. 2009 May;218(1):86-94. PMID: 19197950

- Lo KC, Rossi MR, Burkhardt T, Pomeroy SL, Cowell JK. Overlay analysis of the oligonucleotide array gene expression profiles and copy number abnormalities as determined by array comparative genomic hybridization in medulloblastomas. Genes Chromosomes Cancer. 2007 Jan;46(1):53-66. PMID: 17044047

- Mendrzyk F, Korshunov A, Toedt G, Schwarz F, Korn B, Joos S, Hochhaus A, Schoch C, Lichter P, Radlwimmer B. Isochromosome breakpoints on 17p in medulloblastoma are flanked by different classes of DNA sequence repeats. Genes Chromosomes Cancer. 2006 Apr;45(4):401-10. PMID: 16419060

- Rossi MR, Conroy J, McQuaid D, Nowak NJ, Rutka JT, Cowell JK. Array CGH analysis of pediatric medulloblastomas. Genes Chromosomes Cancer. 2006 Mar;45(3):290-303. PMID: 16320246