Molecular Genetics of Medulloblastoma


Medulloblastoma (MB), the most common malignant paediatric brain tumour, arises in the cerebellum. Recent high‐throughput technology that includes ribonucleic acid‐based expression analysis and deoxyribonucleic acid (DNA)‐based copy number analysis, as well as whole‐genome sequencing studies have unravelled the mysteries of this embryonic tumour from clinical, histological and molecular standpoints. Studies of hereditary syndromes associated with MB have led to an increased understanding of the genomics of this tumour. Signalling pathways and growth factors, which are crucial in normal cerebellum development, are also involved in MB formation. The molecular discoveries in the last decade have led to advances in two major areas: (1) The clinical and molecular subgrouping of patients and their stratification; and (2) research being performed to individualise treatments according to the genetics of the patient's tumour. The use of extensive cancer genetic databases will ensure that future discoveries in MB pathogenesis will be made.

Key Concepts:

  • There is more than one cell of origin for MB.

  • MBs are genetically and histologically heterogeneous.

  • MB growth is similar to the normal growth of the cerebellum but it is growth gone awry.

  • Signalling pathways play significant roles in cerebellar growth. Mutations in these pathways lead to tumour formation.

  • Growth factor and DNA repair pathway mutations may drive MB formation.

  • MB in adults is different from that in children.

  • Metastatic MB has specific genomics that are different from the primary tumour in the same patient.

  • The new molecular discoveries have important prognostication impact.

  • The next era is to individualise novel therapies against each patient's MB.

Keywords: medulloblastoma genetics; Signalling pathways; growth factors; DNA repair pathways; hereditary syndromes; prognostication

Figure 1.

Signalling and growth factor activation pathways implicated in MB formation. Arrows, activators and bars, repressors. Reproduced with permission from Onvani et al. © Expert Reviews Ltd.

Figure 2.

MB subgroups. Pie chart illustrating the frequency, genetics, gene expression of the four subgroups of MB. LCA, large‐cell anaplastic; MBEN, MB with extensive nodularity; M+, positive for metastasis at diagnosis; SHH, sonic hedgehog. Reproduced with permission from Northcott et al. © Nature Publishing Group.



Aldosari N, Bigner SH, Burger PC et al. (2002) MYCC and MYCN oncogene amplification in medulloblastoma. A fluorescence in situ hybridization study on paraffin sections from the Children's Oncology Group. Archives of Pathology and Laboratory Medicine 126(5): 540–544.

Barel D, Avigad S, Mor C et al. (1998) A novel germ‐line mutation in the noncoding region of the p53 gene in a Li‐Fraumeni family. Cancer Genetics and Cytogenetics 103(1): 1–6.

Batra SK, McLendon RE, Koo JS et al. (1995) Prognostic implications of chromosome 17p deletions in human medulloblastomas. Journal of Neuro‐Oncology 24(1): 39–45.

Behesti H and Marino S (2009) Cerebellar granule cells: insights into proliferation, differentiation, and role in medulloblastoma pathogenesis. International Journal of Biochemistry and Cell Biology 41(3): 435–445.

Carlotti CG Jr, Smith C and Rutka JT (2008) The molecular genetics of medulloblastoma: an assessment of new therapeutic targets. Neurosurgical Review 31(4): 359–368.

Clifford SC, Lusher ME, Lindsey JC et al. (2006) Wnt/Wingless pathway activation and chromosome 6 loss characterize a distinct molecular sub‐group of medulloblastomas associated with a favorable prognosis. Cell Cycle 5(22): 2666–2670.

Del Valle L, Enam S, Lassak A et al. (2002) Insulin‐like growth factor I receptor activity in human medulloblastomas. Clinical Cancer Research 8(6): 1822–1830.

Di Marcotullio L, Ferretti E, Greco A et al. (2006) Numb is a suppressor of Hedgehog signalling and targets Gli1 for Itch‐dependent ubiquitination. Nature Cell Biology 8(12): 1415–1423.

Ellison D (2002) Classifying the medulloblastoma: insights from morphology and molecular genetics. Neuropathology and Applied Neurobiology 28(4): 257–282.

Ellison DW, Onilude OE, Lindsey JC et al. (2005) beta‐Catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom Children's Cancer Study Group Brain Tumour Committee. Journal of Clinical Oncology 23(31): 7951–7957.

Fan X, Mikolaenko I, Elhassan I et al. (2004) Notch1 and notch2 have opposite effects on embryonal brain tumor growth. Cancer Research 64(21): 7787–7793.

Fink AJ, Englund C, Daza RA et al. (2006) Development of the deep cerebellar nuclei: transcription factors and cell migration from the rhombic lip. Journal of Neuroscience 26(11): 3066–3076.

Friedrich RE (2007) Diagnosis and treatment of patients with nevoid basal cell carcinoma syndrome (Gorlin‐Goltz syndrome (GGS)). Anticancer Research 27(4A): 1783–1787.

Gilbertson R (2002) Paediatric embryonic brain tumours. Biological and clinical relevance of molecular genetic abnormalities. European Journal of Cancer 38(5): 675–685.

Gilbertson R, Wickramasinghe C, Hernan R et al. (2001) Clinical and molecular stratification of disease risk in medulloblastoma. British Journal of Cancer 85(5): 705–712.

Gilbertson RJ (2004) Medulloblastoma: signalling a change in treatment. Lancet Oncology 5(4): 209–218.

Gilbertson RJ and Clifford SC (2003) PDGFRB is overexpressed in metastatic medulloblastoma. Nature Genetics 35(3): 197–198.

Gilbertson RJ and Ellison DW (2008) The origins of medulloblastoma subtypes. Annual Review of Pathology 3: 341–365.

Griffin CA, Hawkins AL, Packer RJ, Rorke LB and Emanuel BS (1988) Chromosome abnormalities in pediatric brain tumors. Cancer Research 48(1): 175–180.

Huang H, Mahler‐Araujo BM, Sankila A et al. (2000) APC mutations in sporadic medulloblastomas. American Journal of Pathology 156(2): 433–437.

Jagtap P and Szabo C (2005) Poly(ADP‐ribose) polymerase and the therapeutic effects of its inhibitors. Nature Reviews Drug Discovery 4(5): 421–440.

Kool M, Koster J, Bunt J et al. (2008) Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. PLoS One 3(8): e3088.

Korshunov A, Remke M, Werft W et al. (2010) Adult and pediatric medulloblastomas are genetically distinct and require different algorithms for molecular risk stratification. Journal of Clinical Oncology 28(18): 3054–3060.

Kutler DI, Singh B, Satagopan J et al. (2003) A 20‐year perspective on the International Fanconi Anemia Registry (IFAR). Blood 101(4): 1249–1256.

Lamont JM, McManamy CS, Pearson AD, Clifford SC and Ellison DW (2004) Combined histopathological and molecular cytogenetic stratification of medulloblastoma patients. Clinical Cancer Research 10(16): 5482–5493.

Li Y, Lal B, Kwon S et al. (2005) The scatter factor/hepatocyte growth factor: c‐met pathway in human embryonal central nervous system tumor malignancy. Cancer Research 65(20): 9355–9362.

MacDonald TJ, Brown KM, LaFleur B et al. (2001) Expression profiling of medulloblastoma: PDGFRA and the RAS/MAPK pathway as therapeutic targets for metastatic disease. Nature Genetics 29(2): 143–152.

McManamy CS, Lamont JM, Taylor RE et al. (2003) Morphophenotypic variation predicts clinical behavior in childhood non‐desmoplastic medulloblastomas. Journal of Neuropathology and Experimental Neurology 62(6): 627–632.

Miale IL and Sidman RL (1961) An autoradiographic analysis of histogenesis in the mouse cerebellum. Experimental Neurology 4: 277–296.

Morales D and Hatten ME (2006) Molecular markers of neuronal progenitors in the embryonic cerebellar anlage. Journal of Neuroscience 26(47): 12226–12236.

Northcott PA, Fernandez LA, Hagan JP et al. (2009) The miR‐17/92 polycistron is up‐regulated in sonic hedgehog‐driven medulloblastomas and induced by N‐myc in sonic hedgehog‐treated cerebellar neural precursors. Cancer Research 69(8): 3249–3255.

Northcott PA, Korshunov A, Pfister SM and Taylor MD (2012) The clinical implications of medulloblastoma subgroups. Nature Reviews Neurology 8(6): 340–351.

Offit K, Levran O, Mullaney B et al. (2003) Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi anemia. Journal of the National Cancer Institute 95(20): 1548–1551.

Onvani S, Etame AB, Smith CA and Rutka JT (2010) Genetics of medulloblastoma: clues for novel therapies. Expert Review of Neurotherapeutics 10(5): 811–823.

Packer RJ, Rood BR and MacDonald TJ (2003) Medulloblastoma: present concepts of stratification into risk groups. Pediatric Neurosurgery 39(2): 60–67.

Palmer L, Nordborg C, Steneryd K, Aman P and Kyllerman M (2004) Large‐cell medulloblastoma in Aicardi syndrome. Case report and literature review. Neuropediatrics 35(5): 307–311.

Pfister SM, Korshunov A, Kool M et al. (2010) Molecular diagnostics of CNS embryonal tumors. Acta Neuropathologica 120(5): 553–566.

Pomeroy SL, Tamayo P, Gaasenbeek M et al. (2002) Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 415(6870): 436–442.

Reid S, Schindler D, Hanenberg H et al. (2007) Biallelic mutations in PALB2 cause Fanconi anemia subtype FA‐N and predispose to childhood cancer. Nature Genetics 39(2): 162–164.

Rossi A, Caracciolo V, Russo G, Reiss K and Giordano A (2008) Medulloblastoma: from molecular pathology to therapy. Clinical Cancer Research 14(4): 971–976.

Schofield D, West DC, Anthony DC, Marshal R and Sklar J (1995) Correlation of loss of heterozygosity at chromosome 9q with histological subtype in medulloblastomas. American Journal of Pathology 146(2): 472–480.

Stearns D, Chaudhry A, Abel TW et al. (2006) c‐myc overexpression causes anaplasia in medulloblastoma. Cancer Research 66(2): 673–681.

Taniguchi T and D'Andrea AD (2006) Molecular pathogenesis of Fanconi anemia: recent progress. Blood 107(11): 4223–4233.

Taylor MD, Liu L, Raffel C et al. (2002) Mutations in SUFU predispose to medulloblastoma. Nature Genetics 31(3): 306–310.

Taylor MD, Mainprize TG and Rutka JT (2000) Molecular insight into medulloblastoma and central nervous system primitive neuroectodermal tumor biology from hereditary syndromes: a review. Neurosurgery 47(4): 888–901.

Taylor MD, Mainprize TG, Rutka JT et al. (2001) Medulloblastoma in a child with Rubenstein‐Taybi syndrome: case report and review of the literature. Pediatric Neurosurgery 35(5): 235–238.

Taylor MD, Zhang X, Liu L et al. (2004) Failure of a medulloblastoma‐derived mutant of SUFU to suppress WNT signaling. Oncogene 23(26): 4577–4583.

Thompson MC, Fuller C, Hogg TL et al. (2006) Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. Journal of Clinical Oncology 24(12): 1924–1931.

Tong CY, Hui AB, Yin XL et al. (2004) Detection of oncogene amplifications in medulloblastomas by comparative genomic hybridization and array‐based comparative genomic hybridization. Journal of Neurosurgery 100(Suppl. 2): 187–193.

Wu X, Northcott PA, Dubuc A et al. (2012) Clonal selection drives genetic divergence of metastatic medulloblastoma. Nature 482(7386): 529–533.

Yan CT, Kaushal D, Murphy M et al. (2006) XRCC4 suppresses medulloblastomas with recurrent translocations in p53‐deficient mice. Proceedings of the National Academy of Sciences of the USA 103(19): 7378–7383.

Yokota N, Aruga J, Takai S et al. (1996) Predominant expression of human zic in cerebellar granule cell lineage and medulloblastoma. Cancer Research 56(2): 377–383.

Further Reading

Cho YJ, Tsherniak A, Tamayo P et al. (2011) Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. Journal of Clinical Oncology 29(11): 1424–1430.

Northcott PA, Shih DJ, Remke M et al. (2012) Rapid, reliable, and reproducible molecular sub‐grouping of clinical medulloblastoma samples. Acta Neuropathologica 123(4): 615–626.

Northcott PA, Shih DJ, Peacock J et al. (2012) Subgroup‐specific structural variation across 1,000 medulloblastoma genomes. Nature 488(7409): 49–56.

Northcott PA, Rutka JT and Taylor MD (2010) Genomics of medulloblastoma: from Giemsa‐banding to next‐generation sequencing in 20 years. Neurosurgical Focus 28(1): E6.

Parsons DW, Li M, Zhang X et al. (2011) The genetic landscape of the childhood cancer medulloblastoma. Science 331(6016): 435–439.

Remke M, Hielscher T, Northcott PA et al. (2011) Adult medulloblastoma comprises three major molecular variants. Journal of Clinical Oncology 29(19): 2717–2723.

Schwalbe EC, Lindsey JC, Straughton D et al. (2011) Rapid diagnosis of medulloblastoma molecular subgroups. Clinical Cancer Research 17(7): 1883–1894.

Tamayo P, Cho YJ, Tsherniak A et al. (2011) Predicting relapse in patients with medulloblastoma by integrating evidence from clinical and genomic features. Journal of Clinical Oncology 29(11): 1415–1423.

Taylor MD, Northcott PA, Korshunov A et al. (2012) Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathologica 123(4): 465–472.

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Nadi, Mustafa, and Rutka, James(Feb 2013) Molecular Genetics of Medulloblastoma. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0023577]