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
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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.
    Full-text · Article · Apr 2015 · Cell Reports
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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.
    Full-text · Article · Mar 2015 · Cell Reports
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    • "While Sonic Hedgehog (Shh) pathway inhibitors have shown promise in treating medulloblastomas exhibiting Shh pathway hyperactivity [1], these tumors comprise only a subset of medulloblastoma, and few consistent druggable targets have been described among Shh-independent variants of this tumor (e.g. Wnt subgroup, Group 3, and Group 4) [2]–[4]. Our previous studies have revealed the importance of the homeobox transcription factor OTX2 to the maintenance of non-Shh medulloblastomas [5]. "
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    ABSTRACT: Despite an emerging understanding of the genetic alterations giving rise to various tumors, the mechanisms whereby most oncogenes are overexpressed remain unclear. Here we have utilized an integrated approach of genomewide regulatory element mapping via DNase-seq followed by conventional reporter assays and transcription factor binding site discovery to characterize the transcriptional regulation of the medulloblastoma oncogene Orthodenticle Homeobox 2 (OTX2). Through these studies we have revealed that OTX2 is differentially regulated in medulloblastoma at the level of chromatin accessibility, which is in part mediated by DNA methylation. In cell lines exhibiting chromatin accessibility of OTX2 regulatory regions, we found that autoregulation maintains OTX2 expression. Comparison of medulloblastoma regulatory elements with those of the developing brain reveals that these tumors engage a developmental regulatory program to drive OTX2 transcription. Finally, we have identified a transcriptional regulatory element mediating retinoid-induced OTX2 repression in these tumors. This work characterizes for the first time the mechanisms of OTX2 overexpression in medulloblastoma. Furthermore, this study establishes proof of principle for applying ENCODE datasets towards the characterization of upstream trans-acting factors mediating expression of individual genes.
    Full-text · Article · Sep 2014 · PLoS ONE
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