Medulloblastomics revisited: biological and clinical insights from thousands of patients

Abstract

Medulloblastoma, a malignant brain tumour primarily diagnosed during childhood, has recently been the focus of intensive molecular profiling efforts, profoundly advancing our understanding of biologically and clinically heterogeneous disease subgroups. Genomic, epigenomic, transcriptomic and proteomic landscapes have now been mapped for an unprecedented number of bulk samples from patients with medulloblastoma and, more recently, for single medulloblastoma cells. These efforts have provided pivotal new insights into the diverse molecular mechanisms presumed to drive tumour initiation, maintenance and recurrence across individual subgroups and subtypes. Translational opportunities stemming from this knowledge are continuing to evolve, providing a framework for improved diagnostic and therapeutic interventions. In this Review, we summarize recent advances derived from this continued molecular characterization of medulloblastoma and contextualize this progress towards the deployment of more effective, molecularly informed treatments for affected patients.

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Fig. 1: Comparison of MB DNA methylation-derived subtypes described across recent studies.
Fig. 2: Summary of demographic, clinical and molecular features of novel MB subtypes.
Fig. 3: Aberrant signalling pathways implicated in Group 3 and Group 4 MB by proteomics.
Fig. 4: MB subgroup cellular hierarchies deduced from single-cell RNA sequencing.

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Acknowledgements

P.A.N. is a Pew–Stewart Scholar for Cancer Research (Margaret and Alexander Stewart Trust) and recipient of the Sontag Foundation Distinguished Scientist Award. P.A.N. was also supported by the National Cancer Institute (R01CA232143-01), the American Association for Cancer Research (NextGen Grant for Transformative Cancer Research), The Brain Tumour Charity (Quest for Cures and Clinical Biomarkers), the American Lebanese Syrian Associated Charities (ALSAC) and St. Jude. V.H. is supported by a Human Frontier Science Program long-term fellowship (LT000596/2016-L). We acknowledge K. Smith, L. Bihannic and T. Sharma for assistance with data organization and figure design. We thank B. Stelter for assistance with the artwork.

Author information

V.H. and P.A.N researched data for the article, contributed substantially to discussion of the content, wrote the article and reviewed/edited the manuscript before submission. O.A., F.J.S., G.W.R. and S.M.P. researched data for the article, wrote the article and reviewed/edited the manuscript before submission.

Correspondence to Paul A. Northcott.

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The authors declare no competing interests.

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Nature Reviews Cancer thanks T. Curran, E. Ferretti and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Next-generation sequencing

(NGS). Technologies enabling massively parallel reading of amplified short nucleotide sequences (typically yielding hundreds of millions of reads, 100–500 bp in length). In contrast, emerging third-generation sequencing technologies read sequences without prior amplification, yielding much longer reads, albeit with reduced accuracy and throughput.

Molecular classification

Classification of patient tumour samples based on molecular markers, as opposed to classification based on histomorphological appearance.

Intratumoural heterogeneity

The observation that tumours comprise distinct malignant and non-malignant (cells of the microenvironment) cell types. The heterogeneity of malignant cells encompasses genetic heterogeneity (for example, different genetic subclones) and transcriptional heterogeneity (for example, malignant cell states resembling normal development).

Primitive neuroectodermal tumour

(PNET). A class of histologically defined, poorly differentiated childhood brain tumours. More recently, PNET has been reclassified into a number of both novel and previously known brain tumour entities by molecular profiling.

Atypical teratoid rhabdoid tumour

A rare and highly malignant type of childhood brain tumour that is characterized by mutations in the SMARCB1 gene.

Classic histology

The most common histological variant found in all medulloblastoma subgroups, characterized by densely packed small round or oval cells and a high nuclear:cytoplasmic ratio.

Desmoplastic/nodular histology

A histological variant mostly restricted to Sonic hedgehog medulloblastoma, characterized by a varying number of islands of neurocytic differentiation and internodular desmoplasia.

Large-cell/anaplastic (LCA) histology

A histological variant associated with both Group 3 medulloblastoma and a more aggressive phenotype, characterized by the co-occurrence of groups of large cells with round nuclei and cells exhibiting cytological pleomorphism (anaplasia).

Isochromosome

An abnormal chromosome in which both chromosome arms are identical. Isochromosome 17q is one of the most frequent somatic copy-number alterations in Group 3 and Group 4 medulloblastoma. In most cases a second q-arm is fused to the p-arm proximal to the centromere.

Craniospinal axis irradiation

(CSI). Standard therapy for patients with medulloblastoma following surgery, to reduce risk of tumour regrowth and metastatic dissemination. The application of CSI is also associated with neurological impairments and secondary malignancies.

Non-synonymous mutations

Genetic alterations that alter the amino acid sequence of an affected protein, possibly altering protein function. Most described recurrent mutations in medulloblastoma are non-synonymous mutations.

BTB–Kelch protein family

Family of proteins characterized by the presence of an N-terminal BTB domain and C-terminal Kelch motifs. The BTB domain facilitates protein binding, and the Kelch motifs associate to form a β-propeller facilitating protein–protein interactions. This family function as adaptor proteins that link cullin–RING ligases to substrates for ubiquitylation.

Pineal parenchymal tumours of intermediate differentiation

(PPTID). A very rare tumour type of intermediate grade arising from the pineal parenchyma.

Chromothripsis

Clustered occurrence of a large number of structural variants restricted to a single chromosome or chromosomal arm, emerging through a single catastrophic event.

Ptch1+/– mouse MB model

Transgenic mouse model that is heterozygous for the Ptch1 gene. Sporadic Sonic hedgehog medulloblastoma develops in ~15% of Ptch1+/– mice.

Single-cell RNA sequencing

Emerging technology that enables unsupervised characterization of transcriptional profiles in individual cells of healthy and diseased tissues. The throughput of this technology has steadily increased over recent years, now enabling profiling of tens of thousands of individual cells in a single experiment.

Granule neuron progenitor

(GNP). A progenitor cell type that gives rise to granule cells, the most common type of neuron in the mature cerebellum; the presumed developmental origin of Sonic hedgehog medulloblastoma.

Unipolar brush cells

(UBCs). Rare glutamatergic interneurons found in the cerebellar cortex and in the dorsal cochlear nucleus. Recent studies have identified transcriptional similarities between UBCs in mouse and human Group 4 medulloblastoma.

Glutamatergic cerebellar nuclei

(GluCN). Also referred to as deep cerebellar nuclei. Cells that function (along with GABAergic interneurons) as the main output centres of the cerebellum.

Sleeping Beauty transposon system

A synthetic DNA transposon system used for random mutagenesis screening and in a recent Sonic hedgehog-medulloblastoma mouse model. Genes affected by genomic insertion of the transposon can be identified through sequencing.

Bone age

Degree of skeletal maturity, an important parameter for determining the clinical use of SMO inhibitors in patients with Sonic hedgehog medulloblastoma. Prolonged exposure to the targeted inhibitor vismodegib has been associated with growth defects in children that have not reached skeletal maturity.

Patient-derived xenograft

(PDX). A model of cancer in which tumour cells from a patient are implanted and maintained in a non-human carrier, most commonly immunodeficient or humanized laboratory mice. PDX models are thought to resemble patient tumours more closely than cell cultures do.

Blood–brain barrier

A semipermeable border formed by endothelial cells lining the cerebral microvasculature that separates the brain from the circulating blood and protects the brain from fluctuations in plasma composition and from circulating agents such as neurotransmitters and pathogens. The blood–brain barrier also presents a challenge for drug delivery when treating brain tumours.

Blood–tumour barrier

Tumour-associated compromise of the blood–brain barrier, resulting in a highly heterogeneous vasculature characterized by non-uniform permeability to small and large molecules.

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Hovestadt, V., Ayrault, O., Swartling, F.J. et al. Medulloblastomics revisited: biological and clinical insights from thousands of patients. Nat Rev Cancer 20, 42–56 (2020). https://doi.org/10.1038/s41568-019-0223-8

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