Molecular Genetics of Medulloblastoma

Abstract

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.

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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.

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