Article

Integrative Genomic Analysis of Medulloblastoma Identifies a Molecular Subgroup That Drives Poor Clinical Outcome

Harvard University, Cambridge, Massachusetts, United States
Journal of Clinical Oncology (Impact Factor: 18.43). 12/2010; 29(11):1424-30. DOI: 10.1200/JCO.2010.28.5148
Source: PubMed

ABSTRACT Medulloblastomas are heterogeneous tumors that collectively represent the most common malignant brain tumor in children. To understand the molecular characteristics underlying their heterogeneity and to identify whether such characteristics represent risk factors for patients with this disease, we performed an integrated genomic analysis of a large series of primary tumors.
We profiled the mRNA transcriptome of 194 medulloblastomas and performed high-density single nucleotide polymorphism array and miRNA analysis on 115 and 98 of these, respectively. Non-negative matrix factorization-based clustering of mRNA expression data was used to identify molecular subgroups of medulloblastoma; DNA copy number, miRNA profiles, and clinical outcomes were analyzed for each. We additionally validated our findings in three previously published independent medulloblastoma data sets.
Identified are six molecular subgroups of medulloblastoma, each with a unique combination of numerical and structural chromosomal aberrations that globally influence mRNA and miRNA expression. We reveal the relative contribution of each subgroup to clinical outcome as a whole and show that a previously unidentified molecular subgroup, characterized genetically by c-MYC copy number gains and transcriptionally by enrichment of photoreceptor pathways and increased miR-183∼96∼182 expression, is associated with significantly lower rates of event-free and overall survivals.
Our results detail the complex genomic heterogeneity of medulloblastomas and identify a previously unrecognized molecular subgroup with poor clinical outcome for which more effective therapeutic strategies should be developed.

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Available from: Aviad Tsherniak, Aug 26, 2015
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    • "Please cite this article in press as: Penas et al., Casein Kinase 1d Is an APC/C Cdh1 Substrate that Regulates Cerebellar Granule Cell Neurogenesis, Cell Reports (2015), http://dx.doi.org/10.1016/j.celrep.2015.03.016 et al., 2006; Taylor et al., 2002; Yauch et al., 2009). Group 3 (G3) medulloblastoma, the most aggressive form of the disease , is associated with MYC overexpression (Cho et al., 2011; Ellison et al., 2011; Northcott et al., 2011; Pfister et al., 2009). Recent sequencing studies have demonstrated CK1d overexpression in G3 medulloblastoma, suggesting a role for CK1 isoforms in some medulloblastoma subgroups (Gibson et al., 2010; Jones et al., 2012; Northcott et al., 2012; Pugh et al., 2012; Robinson et al., 2012). "
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    ABSTRACT: Although casein kinase 1δ (CK1δ) is at the center of multiple signaling pathways, its role in the expansion of CNS progenitor cells is unknown. Using mouse cerebellar granule cell progenitors (GCPs) as a model for brain neurogenesis, we demonstrate that the loss of CK1δ or treatment of GCPs with a highly selective small molecule inhibits GCP expansion. In contrast, CK1δ overexpression increases GCP proliferation. Thus, CK1δ appears to regulate GCP neurogenesis. CK1δ is targeted for proteolysis via the anaphase-promoting complex/cyclosome (APC/C(Cdh1)) ubiquitin ligase, and conditional deletion of the APC/C(Cdh1) activator Cdh1 in cerebellar GCPs results in higher levels of CK1δ. APC/C(Cdh1) also downregulates CK1δ during cell-cycle exit. Therefore, we conclude that APC/C(Cdh1) controls CK1δ levels to balance proliferation and cell-cycle exit in the developing CNS. Similar studies in medulloblastoma cells showed that CK1δ holds promise as a therapeutic target. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 04/2015; 44(2). DOI:10.1016/j.celrep.2015.03.016 · 8.36 Impact Factor
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    • "Please cite this article in press as: Penas et al., Casein Kinase 1d Is an APC/C Cdh1 Substrate that Regulates Cerebellar Granule Cell Neurogenesis, Cell Reports (2015), http://dx.doi.org/10.1016/j.celrep.2015.03.016 et al., 2006; Taylor et al., 2002; Yauch et al., 2009). Group 3 (G3) medulloblastoma, the most aggressive form of the disease , is associated with MYC overexpression (Cho et al., 2011; Ellison et al., 2011; Northcott et al., 2011; Pfister et al., 2009). Recent sequencing studies have demonstrated CK1d overexpression in G3 medulloblastoma, suggesting a role for CK1 isoforms in some medulloblastoma subgroups (Gibson et al., 2010; Jones et al., 2012; Northcott et al., 2012; Pugh et al., 2012; Robinson et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Although casein kinase 1δ (CK1δ) is at the center of multiple signaling pathways, its role in the expansion of CNS progenitor cells is unknown. Using mouse cerebellar granule cell progenitors (GCPs) as a model for brain neurogenesis, we demonstrate that the loss of CK1δ or treatment of GCPs with a highly selective small molecule inhibits GCP expansion. In contrast, CK1δ overexpression increases GCP proliferation. Thus, CK1δ appears to regulate GCP neurogenesis. CK1δ is targeted for proteolysis via the anaphase-promoting complex/cyclosome (APC/CCdh1) ubiquitin ligase, and conditional deletion of the APC/CCdh1 activator Cdh1 in cerebellar GCPs results in higher levels of CK1δ. APC/CCdh1 also downregulates CK1δ during cell-cycle exit. Therefore, we conclude that APC/CCdh1 controls CK1δ levels to balance proliferation and cell-cycle exit in the developing CNS. Similar studies in medulloblastoma cells showed that CK1δ holds promise as a therapeutic target.
    Cell Reports 03/2015; · 8.36 Impact Factor
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    • "34. Cho YJ, et al. (2011) "
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