Abstract
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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Acknowledgments
XW is supported by a CIHR Vanier Canada Graduate Scholarship, McLaughlin Centre for Molecular Medicine MD/PhD Scholarship, and the Ruggles MD/PhD Innovation Award. MDT is supported by a CIHR Clinician Scientist Phase II award, funds from the Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children and The University of Toronto, and operating funds from the Canadian Institutes of Health Research, the National Institutes of Health (R01CA159859 and R01CA148699) and the Pediatric Brain Tumor Foundation. VR is supported by a CIHR fellowship, an Alberta Innovates-Health Solutions Clinical Fellowship and a Young Investigator Award from Alex’s Lemonade Stand Foundation. BHK is supported by the Gattuso-Slaight Personalized Cancer Medicine Fund at the Princess Margaret Cancer Centre. We wish to acknowledge the Labatt Brain Tumour Research Centre and Tumour Tissue Repository, which are supported by b.r.a.i.n.child and Meagan’s Walk.
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X. Wang and A. M. Dubuc contributed equally to this work.
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401_2015_1389_MOESM1_ESM.eps
Supplementary material 1 (EPS 1542 kb) Supplementary Fig. 1 PCA of the primary and metastatic medulloblastoma samples described in using the 1,000 most differentially expressed genes (a) and 10,000 most differentially methylated probes (b). Coloured ellipsoids (red = SHH, yellow = Group 3, green = Group 4) represent 1.5 SDs of the data distribution for each subgroup. Individual patients are indicated with a unique colour
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Supplementary material 2 (DOCX 25 kb) Supplementary Table 1. Medulloblastoma subgroup predictions and consensus using integrative genomics analysis based on gene expression and 450k DNA methylation
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Supplementary material 3 (XLSX 60 kb) Supplementary Table 2. Detailed demographic, clinical, and histological characteristics of patients
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Wang, X., Dubuc, A.M., Ramaswamy, V. et al. Medulloblastoma subgroups remain stable across primary and metastatic compartments. Acta Neuropathol 129, 449–457 (2015). https://doi.org/10.1007/s00401-015-1389-0
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DOI: https://doi.org/10.1007/s00401-015-1389-0