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Comprehensive molecular profiling identifies novel genetic drivers and subtypes underlying medulloblastoma

Current therapies for medulloblastoma (MB), a highly malignant childhood brain tumor, impose debilitating effects on the developing child, warranting the development of molecularly targeted treatments with reduced toxicities. Prior studies have failed to disclose the full spectrum of driver genes and molecular processes operative in MB or adequately explain heterogeneity among molecular subgroups. Herein, we detail the somatic landscape across 491 sequenced MBs and molecular heterogeneity amongst 1,256 epigenetically analyzed cases, identifying subgroup-specific mutational signatures, driver genes, and pathway alterations including previously unappreciated actionable therapeutic targets. Integrative approaches for assigning driver genes to subgroups explained >65-70% of Group 3 and Group 4, doubling previous knowledge. Novel subtypes underlying Group 3 and Group 4 were differentially enriched for specific driver events, including hotspot in-frame indels targeting KBTBD4 and ‘enhancer hijacking’ driving activation of PRDM6. Thus, application of integrative genomics to an unprecedented cohort of clinical samples derived from a single childhood cancer entity has disclosed a series of new cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for treating MB.

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID Description Technology Samples
EGAD00001003125 224
EGAD00001003126 74
EGAD00001003127 482
EGAD00001003128 35
EGAD00001003279 Illumina HiSeq 2000 171
EGAD00010001300 Affymetrix expression array 146
EGAD00010001301 Affymetrix expression array 246
EGAD00010001319 Illumina Infinium HumanMethylation450 BeadChip 345
EGAD00010001323 Illumina Infinium HumanMethylation450 BeadChip 911
Publications Citations
The whole-genome landscape of medulloblastoma subtypes.
Nature 547: 2017 311-317
Extra-mitochondrial prosurvival BCL-2 proteins regulate gene transcription by inhibiting the SUFU tumour suppressor.
Nat Cell Biol 19: 2017 1226-1236
Proteomics, Post-translational Modifications, and Integrative Analyses Reveal Molecular Heterogeneity within Medulloblastoma Subgroups.
Cancer Cell 34: 2018 396-410.e8
Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma.
Nature 574: 2019 707-711
The transcriptional landscape of Shh medulloblastoma.
Nat Commun 12: 2021 1749
Identification of ITPR1 as a Hub Gene of Group 3 Medulloblastoma and Coregulated Genes with Potential Prognostic Values.
J Mol Neurosci 72: 2022 633-641
Failure of human rhombic lip differentiation underlies medulloblastoma formation.
Nature 609: 2022 1021-1028
Linked-read based analysis of the medulloblastoma genome.
Front Oncol 13: 2023 1221611
Compartments in medulloblastoma with extensive nodularity are connected through differentiation along the granular precursor lineage.
Nat Commun 15: 2024 269
Childhood cancer mutagenesis caused by transposase-derived PGBD5.
Sci Adv 10: 2024 eadn4649