Article

Subgroup-specific structural variation across 1,000 medulloblastoma genomes

Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada.
Nature (Impact Factor: 42.35). 07/2012; 488(7409):49-56. DOI: 10.1038/nature11327
Source: PubMed

ABSTRACT Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy.

Download full-text

Full-text

Available from: Giuseppe Cinalli, Aug 25, 2015
0 Followers
 · 
991 Views
  • Source
    • "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). CK1d is expressed in mouse cerebellum (Lö hler et al., 2009), an opportune model for CNS neurogenesis. "
    [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/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
  • Source
    • "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). CK1d is expressed in mouse cerebellum (Lö hler et al., 2009), an opportune model for CNS neurogenesis. "
    [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
  • Source
    • "MYC is misregulated in the majority of human cancers , leading to uncontrolled proliferation possible through augmentation of existing gene expression programs (Lin et al., 2012). In contrast to MYC, MYCN and MYCL misregulation occurs only in high-risk cancers of neuroendocrine origin, such as SCLC (Huijbers et al., 2014; Johnson et al., 1987; McFadden et al., 2014), neuroblastoma (MYCN) (Huang and Weiss, 2013), and medulloblastoma (MYCN, MYCL) (Northcott et al., 2012). Moreover, many SCLC tumors have focal amplifications or increased expression of SOX-family genes (Voortman et al., 2010), including SOX2, which is critical for lung development and self-renewal. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Small cell lung cancer (SCLC) is an aggressive disease with high mortality, and the identification of effective pharmacological strategies to target SCLC biology represents an urgent need. Using a high-throughput cellular screen of a diverse chemical library, we observe that SCLC is sensitive to transcription-targeting drugs, in particular to THZ1, a recently identified covalent inhibitor of cyclin-dependent kinase 7. We find that expression of super-enhancer-associated transcription factor genes, including MYC family proto-oncogenes and neuroendocrine lineage-specific factors, is highly vulnerability to THZ1 treatment. We propose that downregulation of these transcription factors contributes, in part, to SCLC sensitivity to transcriptional inhibitors and that THZ1 represents a prototype drug for tailored SCLC therapy. Copyright © 2014 Elsevier Inc. All rights reserved.
    Cancer Cell 12/2014; 26(6):909-22. DOI:10.1016/j.ccell.2014.10.019 · 23.89 Impact Factor
Show more