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.

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Available from: Giuseppe Cinalli, Jul 15, 2015
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    • "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. "
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    • "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. "
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    • "WNT subgroup (10–15% of all meduloblastomas) is characterized by classic histology (Kool et al. 2012), age above 3 years, good prognosis and infrequent metastasis (Li et al. 2013). Genetic analyses have shown the enrichment of genes of WNT signaling pathway (adenomatous polyposis coli – APC, CTNN1, AXIN1, MYC, JUN, FRA, AXIN2, SMARCA4, CREBBP, MED13, CCND1 genes), CTNNB1 mutation, DDX3X mutations and loss of chromosome 6 (Kool et al. 2012; Northcott et al. 2012; Pugh et al. 2012; Robinson et al. 2012; Min et al. 2013). Loss of chromosome 6 is associated with 88% of WNT tumors (Schwalbe et al. 2011). "
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