Medulloblastomics: the end of the beginning

Key Points

  • Medulloblastoma is the most common malignant paediatric brain tumour and is a leading cause of cancer-related morbidity and mortality in children.

  • Integrative genomic studies have recently identified at least four distinct molecular subgroups of medulloblastoma — WNT, sonic hedgehog (SHH), Group 3 and Group 4 — which exhibit highly discriminate transcriptional, cytogenetic and mutational spectra in addition to divergent patient demographics and clinical behaviour.

  • Recent next-generation sequencing of medulloblastoma samples and their matched constitutional DNA has led to the identification of a multitude of previously unknown candidate genes that are somatically mutated in this cancer, including many that are mutated in a subgroup-specific manner.

  • Different mechanisms of structural variation, including somatic copy number aberrations, chromothripsis and tetraploidy, contribute to a considerable proportion of medulloblastomas and may be more prevalent than recurrent somatic mutations in Group 3 and Group 4 tumours.

  • Despite the extensive amount of copy number and sequence data that has become available for large cohorts of medulloblastoma, most Group 3 and Group 4 tumours cannot be attributed to a specific driver mutation or mutations, suggesting that additional mechanisms, such as epigenetic deregulation, may also have a prominent role.

  • Research on medulloblastoma during the next few years will be focused on the functional validation of candidate genes and molecular processes that were reported to be deregulated in the recent human genomic studies. The generation of faithful models that recapitulate these mutational events will become a priority, and such reagents will be a valuable resource for the development of rational, molecularly targeted therapies.

Abstract

The division of medulloblastoma into different subgroups by microarray expression profiling has dramatically changed our perspective of this malignant childhood brain tumour. Now, the availability of next-generation sequencing and complementary high-density genomic technologies has unmasked novel driver mutations in each medulloblastoma subgroup. The implications of these findings for the management of patients are readily apparent, pinpointing previously unappreciated diagnostic and therapeutic targets. In this Review, we summarize the 'explosion' of data emerging from the application of modern genomics to medulloblastoma, and in particular the recurrent targets of mutation in medulloblastoma subgroups. These data are currently making their way into clinical trials as we seek to integrate conventional and molecularly targeted therapies.

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Figure 1: Meta-analysis of medulloblastoma next-generation sequencing studies.
Figure 2: Novel mutations and genomic targets in medulloblastoma subgroups.
Figure 3: Convergent deregulation of the histone code in medulloblastoma.
Figure 4: Correlation of cytogenetic alterations and somatic mutations in Group 3 and Group 4 medulloblastoma.

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Acknowledgements

This work was principally supported by the PedBrain Tumour Project contributing to the International Cancer Genome Consortium (ICGC), funded by German Cancer Aid (109252) and the German Federal Ministry of Education and Research (BMBF, NGFNplus #01GS0883). The authors also acknowledge the Pediatric Brain Tumour Foundation (PBTFUS), the US National Institutes of Health (R01CA148699 and R01CA159859) and the Dutch Cancer Foundations KWF (2010-4713) and KIKA. P.A.N. is a Roman Herzog PostDoctoral Fellow supported by the Hertie Foundation and the DKFZ. The authors are deeply indebted to C. Smith of Creative Science Studios for assistance with artwork. They also acknowledge C. Imbusch (DKFZ) for bioinformatic support pertaining to the meta-analysis of next-generation sequencing studies. Last, special acknowledgments are warranted for T. J. Pugh (Broad Institute), N. Jäger (DKFZ) and D. J. H. Shih (SickKids) who played lead bioinformatic roles in the respective medulloblastoma genomic studies highlighted in this Review.

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Correspondence to Michael D. Taylor or Stefan M. Pfister.

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Glossary

Leptomeningeal dissemination

Metastasis to the leptomeninges (arachnoid mater and pia mater) that wrap the brain and spinal cord. Metastatic medulloblastoma cells typically disseminate to the leptomeninges via the cerebrospinal fluid.

Gorlin syndrome

Also known as nevoid basal cell carcinoma syndrome (NBCCS). An autosomal dominant condition in which affected individuals harbour germline mutations in patched 1 and the cells of which display aberrant activation of the sonic hedgehog signalling pathway. Individuals exhibit a variety of developmental defects including jaw cysts, palmar pits and skeletal abnormalities and they are predisposed to the development of extensive basal cell carcinomas and medulloblastoma, among other cancers.

Turcot syndrome

Typically an autosomal dominant condition characterized by multiple adenomatous colon polyps and predisposition to colorectal cancer and brain tumours. The genetic basis is linked to mutations in adenomatous polyposis coli, which predisposes to medulloblastoma, or to the mismatch repair genes MLH1 or PMS2, which predispose to glioblastoma.

Next-generation sequencing

Sequencing technologies emerging since 2005 that have substantially increased the output of the nucleic acid sequencing process. They produce millions to hundreds of millions of typically short sequence reads (50–400 bp) from amplified DNA clones.

Classic histology

The most common histological subtype of medulloblastoma, displaying prototypical sheets of repetitive small cells with a high nuclear/cytoplasmic ratio and round nuclei. Found in all medulloblastoma subgroups.

External granule cell layer

(EGL). A germinal zone comprised of cerebellar granule neuron precursors that line the surface of the developing cerebellum.

Lower rhombic lip

(LRL). A division of the rhombic lip, a specialized germinal matrix situated at the interface between the neural tube and the roofplate of the fourth ventricle of the developing cerebellum.

Dorsal brainstem

The hindmost parts of the structure of the brainstem.

Desmoplastic (or nodular) histology

Histological variant of medulloblastoma characterized by the presence of a varying number of nodules that consist of differentiated neurocytic cells and internodular desmoplasia (fibrous or connective tissue), best demonstrated by reticulin staining. Mostly restricted to the sonic hedgehog medulloblastoma subgroup.

Large-cell or anaplastic

(LCA). An admixture of two usually co-occuring histological variants of medulloblastoma associated with a more aggressive clinical phenotype and the Group 3 subgroup. Collectively, LCA medulloblastomas appear as groups of large cells with round nuclei (large cell) and cells exhibiting marked cytological pleomorphisms (anaplasia), especially nuclear pleomorphism.

Cerebellar granule neuron precursors

(CGNPs). As precursors to the most abundant neuron in the brain, CGNPs arise in the hindbrain during late embryonic development and migrate postnatally to the external granule cell layer of the cerebellum. They then undergo a period of massive proliferation before eventually migrating inwards to the internal granule layer and terminally differentiating.

Cochlear nuclei

Structures in the brainstem that derive from the auditory lower rhombic lip, receiving inputs on sound from the cochlear nerve. Cerebellar granule neuron precursors residing in the cochlear nuclei have been implicated as a possible cell-of-origin for sonic hedgehog medulloblastoma.

Isochromosome

An abnormal chromosome produced during mitosis or meiosis that is characterized by the presence of two genetically and morphologically identical chromosome arms fused at the centromere. Strictly, the common alteration of chromosome 17 in medulloblastoma is more often an isodicentric (17q), as the breakpoint is typically in the p-arm proximal to the centromere rather than at the centromere itself.

Single nucleotide variants

(SNVs). A nucleotide substitution resulting in the exchange of one nucleotide for another. In cancer, SNVs refer to single nucleotide changes present in the tumour DNA that are not present in the patient's normal genome.

Indels

Mutations involving the insertion or deletion of nucleotides, which often lead to a loss of function by causing a shift in the reading frame of a gene.

Chromothripsis

A process of erroneous DNA repair following a single catastrophic breakage event that results in massive genomic rearrangement.

Tetraploidy

A whole-genome duplication event such that each chromosome is present as four, rather than two, copies.

Lewy bodies

Abnormal protein aggregates found in the brain of individuals with Parkinson's disease, Lewy body dementia and other related disorders.

Tandem duplication

A structural variant caused by a duplication event that results in two genomic segments of at least 1 kb in size that share >90% sequence identity positioned in a contiguous manner within the genome.

Double-minute chromosomes

Typically acentric, extra-chromosomally amplified chromatin, usually containing a particular chromosomal segment or gene. Double minutes are common in cancer and often result in oncogene amplification through replication and asymmetric distribution after cell division.

Single nucleotide polymorphism

(SNP). A single nucleotide DNA sequence variant that differs between individuals or paired chromosomes from the same individual. In contrast to single nucleotide variants, these are present in the normal genome of an individual.

Aneuploidy

An abnormal number of chromosomes.

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Northcott, P., Jones, D., Kool, M. et al. Medulloblastomics: the end of the beginning. Nat Rev Cancer 12, 818–834 (2012). https://doi.org/10.1038/nrc3410

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