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.

Figure 1 |. Comparison of MB DNA methylation-derived subtypes described across recent studies.

a | Correspondence between four molecular subtypes of the SHH-MB subgroup described by Cavalli et al. and the subtypes described in three additional studies. DNA methylation profiles from all samples of each additional study were used to classify patients into the four molecular subtypes using a machine learning approach. The height of each row corresponds to the fraction of samples per subtype in the Cavalli et al. study. Percentages indicate overlap of predicted subtypes with original subtype annotations in each additional study. No samples from the study by Robinson et al. predicted as SHH-δ, because the study only included patients under the age of six years. b | Similar comparison between the eight molecular subtypes of Group 3/4-MB described by Northcott et al. and Sharma et al. and the subtypes described in two additional studies. Line width between consensus subgroups and DNA methylation subtypes indicate the fraction of samples per subtype originally classified as Group 3- or Group 4-MB.

Figure 2 |. Summary of demographic, clinical, and molecular features of novel MB subtypes.

Values for age and gender distribution, frequency of metastasis, and 5-year overall survival for the WNT and SHH subgroups are derived from the Cavalli et al. study. Driver events were additionally derived from the Kool et al. and Robinson et al. studies. Similarly, values for the Group 3 and Group 4 subgroups were derived from the Sharma et al. study. OS, overall survival; LCA, large cell anaplastic; MBEN, medulloblastoma with extensive nodularity; i17q, isochromosome 17q; BCOR, BCL6 Corepressor; CTDNEP1, CTD Nuclear Envelope Phosphatase 1; CTNNB1, Catenin Beta 1; DDX3X, DEAD-Box Helicase 3 X-Linked; GFI1, Growth Factor Independent 1 Transcriptional Repressor; GFI1B, Growth Factor Independent 1B Transcriptional Repressor; GLI2, GLI Family Zinc Finger 2; KBTBD4, Kelch Repeat and BTB Domain Containing 4; KDM6A, Lysine Demethylase 6A (UTX); KMT2C, Lysine Methyltransferase 2C (MLL3); KMT2D, Lysine Methyltransferase 2D (MLL2); MYC, MYC Proto-Oncogene BHLH Transcription Factor; MYCN, MYCN Proto-Oncogene BHLH Transcription Factor; OTX2, Orthodenticle Homeobox 2; PRDM6, PR/SET Domain 6; PTCH1, Patched 1; PTEN, Phosphatase and Tensin Homolog; SMARCA4, SWI/SNF Related Matrix Associated Actin Dependent Regulator of Chromatin Subfamily A Member 4; SMO, Smoothened Frizzled Class Receptor; SUFU, SUFU Negative Regulator of Hedgehog Signaling; TERT, Telomerase Reverse Transcriptase; TP53, Tumour Protein P53; ZMYM3, Zinc Finger MYM-Type Containing 3.

Figure 3 |. Recurrently altered genes and pathways across MB subgroups.

Grouped barplot of recurrently altered genes identified in WNT- (blue), SHH- (red), Group 3- (yellow) and Group 4-MB (green). Altered genes are grouped by functional categories. The percentage of affected samples is indicated (y-axis). Mutations of CTNNB1 are identified in 85.7% of WNT-MB.

Figure 4 |. Aberrant signaling pathways implicated in Group 3 and Group 4 MB by proteomics.

Colors indicate the relative abundance in mRNA (left part), protein and phosphoprotein (right part) between Group 4 and Group 3. Phosphorylation is indicated as a small circle. The half circle indicates the plasma membrane.