Journal
ACTA NEUROPATHOLOGICA
Volume 129, Issue 3, Pages 449-457Publisher
SPRINGER
DOI: 10.1007/s00401-015-1389-0
Keywords
Medulloblastoma; Metastasis; Molecular subgroups; Integrative genomics; Gene expression; DNA methylation
Categories
Funding
- CIHR Vanier Canada Graduate Scholarship
- McLaughlin Centre for Molecular Medicine MD/PhD Scholarship
- Ruggles MD/PhD Innovation Award
- CIHR Clinician Scientist Phase II award
- Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children
- University of Toronto
- Canadian Institutes of Health Research
- National Institutes of Health [R01CA159859, R01CA148699]
- Pediatric Brain Tumor Foundation
- CIHR
- Alberta Innovates-Health Solutions Clinical Fellowship
- Young Investigator Award from Alex's Lemonade Stand Foundation
- Gattuso-Slaight Personalized Cancer Medicine Fund at the Princess Margaret Cancer Centre
- b.r.a.i.n.child
- Meagan's Walk
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Medulloblastoma comprises four distinct molecular variants with distinct genetics, transcriptomes, and outcomes. Subgroup affiliation has been previously shown to remain stable at the time of recurrence, which likely reflects their distinct cells of origin. However, a therapeutically relevant question that remains unanswered is subgroup stability in the metastatic compartment. We assembled a cohort of 12-paired primary-metastatic tumors collected in the MAGIC consortium, and established their molecular subgroup affiliation by performing integrative gene expression and DNA methylation analysis. Frozen tissues were collected and profiled using Affymetrix gene expression arrays and Illumina methylation arrays. Class prediction and hierarchical clustering were performed using existing published datasets. Our molecular analysis, using consensus integrative genomic data, establishes the unequivocal maintenance of molecular subgroup affiliation in metastatic medulloblastoma. We further validated these findings by interrogating a non-overlapping cohort of 19 pairs of primary-metastatic tumors from the Burdenko Neurosurgical Institute using an orthogonal technique of immunohistochemical staining. This investigation represents the largest reported primary-metastatic paired cohort profiled to date and provides a unique opportunity to evaluate subgroup-specific molecular aberrations within the metastatic compartment. Our findings further support the hypothesis that medulloblastoma subgroups arise from distinct cells of origin, which are carried forward from ontogeny to oncology.
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