The whole-genome landscape of medulloblastoma subtypes

Abstract

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

Basal Suppression of the Sonic Hedgehog Pathway by the G-Protein-Coupled Receptor Gpr161 Restricts Medulloblastoma Pathogenesis

“…In addition, we did not detect any homozygous deletions in the Gpr161 locus in 827 patients tested (Northcott et al, 2017), implying that this locus is not a common hotspot for tumor initiation in patients. However, upon reevaluating the expression of GPR161 from previously published expression data (Cho et al, 2011) with patient survival, we noted that the expression levels of GPR161 tightly correlated with decreased patient survival length only in the SHH-MB subtype but not in other subtypes combined (Figures 2H and S2C).…”

UAB30, a novel RXR agonist, decreases tumorigenesis and leptomeningeal disease in group 3 medulloblastoma patient-derived xenografts

“…By 2012, consensus emerged that there are at least four distinct molecular subgroups of MB that differ in their demographics, transcriptomes, somatic genetic events, and clinical outcomes [53]. More recent data have emerged to indicate that significant molecular heterogeneity exists within the four subgroups [54]. These findings are leading to major changes in risk stratification of MB patients and clinical trial designs have already begun to be altered centered on these changes.…”

The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants

“…Now, whole genome sequencing can capture all of the genes (about 1% of the whole genome) and most of the rest of the genome in a single experiment, with the potential to recognize all types of genetic variation and thereby usurp the less comprehensive technologies (Box 1). 2 Information from whole genome sequencing can already identify the molecular causes of suspected heritable conditions and cancer; [2][3][4][5][6][7] however, we anticipate that genomic analysis will become a standard component of proactive health care, given its potential to identify predisposition to medically actionable conditions, explain uncharacterized disease and reveal carriers for recessive disorders and predictors of medication safety and response. 8 Interpretation of sequence data remains challenging, with unknown clinical utility and predictive value among the general population.…”