Detection of oncogene amplifications in medulloblastomas by comparative genomic hybridization and array-based comparative genomic hybridization

Tong, Cindy S.W.; Hui, Angela B.; Yin, Xiao; Pang, Jesse C.S.; Zhu, Xian Lun; Poon, Wai Sang; Ng, Ho Keung

doi:10.3171/ped.2004.100.2.0187

Cited by 69 publications

(62 citation statements)

References 36 publications

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“…We hypothesize that inactivation of the P53 pathway is one of the potential mechanisms in medulloblastoma to prevent OTX2-induced senescence. However, P53 mutation or amplification of MDM2, which inhibits P53, has been infrequently reported for medulloblastoma (20,(43)(44)(45)(46). However, PPM1D, shown to inhibit P53 in medulloblastoma, is highly overexpressed in most medulloblastoma and even amplified in some (9,(47)(48)(49).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Cell Cycle Genes and Induction of Senescence by Overexpression of OTX2 in Medulloblastoma Cell Lines

Bunt

Haas

Hasselt

et al. 2010

Molecular Cancer Research

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The transcription factor orthodenticle homeobox 2 (OTX2) has been implicated in the pathogenesis of medulloblastoma, as it is often highly expressed and sometimes amplified in these tumors. Little is known of the downstream pathways regulated by OTX2. We therefore generated MED8A and DAOY medulloblastoma cell lines with doxycycline-inducible OTX2 expression. In both cell lines, OTX2 inhibited proliferation and induced a senescencelike phenotype with senescence-associated β-galactosidase activity. Expression profiles of time series after OTX2 induction in MED8A showed early upregulation of cell cycle genes related to the G 2 -M phase, such as AURKA, CDC25C, and CCNG2. Paradoxically, G 1 -S phase genes such as MYC, CDK4, CDK6, CCND1, and CCND2 were strongly downregulated, in line with the observed G 1 arrest. ChIP-on-chip analyses of OTX2 binding to promoter regions in MED8A and DAOY showed a strong enrichment for binding to the G 2 -M genes, suggesting a direct activation. Their mRNA expression correlated with OTX2 expression in primary tumors, underscoring the in vivo relevance of this regulation. OTX2 induction activated the P53 pathway in MED8A, but not in DAOY, which carries a mutated P53 gene. In DAOY cells, senescence-associated secretory factors, such as interleukin-6 and insulin-like growth factor binding protein 7, were strongly upregulated after OTX2 induction. We hypothesize that the imbalance in cell cycle stimulation by OTX2 leads to cellular senescence either by activating the P53 pathway or through the induction of secretory factors. Our data indicate that OTX2 directly induces a series of cell cycle genes but requires cooperating genes for an oncogenic acceleration of the cell cycle.

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Section: Discussionmentioning

confidence: 99%

Regulation of Cell Cycle Genes and Induction of Senescence by Overexpression of OTX2 in Medulloblastoma Cell Lines

Bunt

Haas

Hasselt

et al. 2010

Molecular Cancer Research

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“…Previous studies have demonstrated 17p loss in 25-50% medulloblastomas, but not in AT/RT. 5,6 Rorke et al further found that the chromosomal abnormality identified in a subset of AT/RT is monosomy or contains a deletion of chromosome 22. 7 Recent studies reported that a CNS rhaboid tumor with an unbalanced 9;22 translocation leads to loss of 22q11.…”

mentioning

confidence: 99%

Increased expression of osteopontin gene in atypical teratoid/rhabdoid tumor of the central nervous system

et al. 2005

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The atypical teratoid/rhabdoid tumor, primary to the central nervous system, is a highly malignant and aggressive neoplasm of infancy and childhood. Although having distinct biological features and clinical outcomes, it is frequently misdiagnosed as primitive neuroectodermal tumor/medulloblastoma. To further distinguish the underlying pathogenesis and to identify biological markers for clinical use, an atypical teratoid/ rhabdoid tumor-derived cell line was established and its gene expression pattern analyzed in comparison to the human astrocyte SVG12 cell line and the human DAOY medulloblastoma cell line using a complementary DNA microarray method. The osteopontin gene was found specifically upregulated in atypical teratoid/rhabdoid tumor cells. This specificity was confirmed by immunohistochemistry in pathological sections of tissues from atypical teratoid/rhabdoid tumor patients. Even though the role of osteopontin in the cytopathogenesis of atypical teratoid/rhabdoid tumor still needs to be determined, our data support that overexpressed osteopontin is a potential diagnostic marker for atypical teratoid/rhabdoid tumor.

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“…A number of proto-oncogenes in MB such as CDK6, PDGFRA, KIT and MYCL1 have been found to be amplified by array CGH. A single copy numbers gains of MET locus on chromosome 7q in 38.5% of the cases in 13 MBs (MacBabe 2006;Tong et al 2004). The Notch pathway was found to be implicated in MBs pathogenesis in a number of studies.…”

Section: Genetic Alterations and Its Corroletion With Clinicohistopatmentioning

confidence: 99%

Medulloblastoma – Genetic Alterations

Manor¹,

Bodner²

2011

Molecular Targets of CNS Tumors

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Detection of oncogene amplifications in medulloblastomas by comparative genomic hybridization and array-based comparative genomic hybridization

Cited by 69 publications

References 36 publications

Regulation of Cell Cycle Genes and Induction of Senescence by Overexpression of OTX2 in Medulloblastoma Cell Lines

Regulation of Cell Cycle Genes and Induction of Senescence by Overexpression of OTX2 in Medulloblastoma Cell Lines

Increased expression of osteopontin gene in atypical teratoid/rhabdoid tumor of the central nervous system

Medulloblastoma – Genetic Alterations

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