Genomic Profiling Identifies Discrete Deletions Associated with Translocations in Glioblastoma Multiforme

Mulholland, Paul J.; Fiegler, Heike; Mazzanti, Chiara Maria; Gorman, Patricia; Sasieni, Peter; Adams, Jo; Jones, Tania; Babbage, Jane W; Vatcheva, Radost; Ichimura, Koichi; East, Philip; Poullikas, Chrysanthos; Collins, V. Peter; Carter, Nigel P.; Tomlinson, Ian; Sheer, Denise

doi:10.4161/cc.5.7.2631

Cited by 60 publications

(37 citation statements)

References 36 publications

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“…Deletion of ∼165 Mb of chromosome 6q25-27 in GBM involving IGF2R, PARK2, PACRG, and QKI was found by CGH (40). Our SNP-Chip data showed that 16 of 55 (29%) GBM samples had deletion of chromosome 6q and two of these samples had a homozygous deletion (4%) at 6q26-27, which included the PARK2, PACRG, QKI, and PDE10A genes.…”

Section: Discussionmentioning

confidence: 89%

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High-Resolution Genomic Copy Number Profiling of Glioblastoma Multiforme by Single Nucleotide Polymorphism DNA Microarray

Ding

Ogawa

Kawamata

et al. 2009

Molecular Cancer Research

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Glioblastoma multiforme (GBM) is an extremely malignant brain tumor. To identify new genomic alterations in GBM, genomic DNA of tumor tissue/explants from 55 individuals and 6 GBM cell lines were examined using single nucleotide polymorphism DNA microarray (SNP-Chip). Further gene expression analysis relied on an additional 56 GBM samples. SNP-Chip results were validated using several techniques, including quantitative PCR (Q-PCR), nucleotide sequencing, and a combination of Q-PCR and detection of microsatellite markers for loss of heterozygosity with normal copy number [acquired uniparental disomy (AUPD)]. Whole genomic DNA copy number in each GBM sample was profiled by SNP-Chip. Several signaling pathways were frequently abnormal. Either the p16(INK4A)/p15(INK4B)-CDK4/6-pRb or p14(ARF)-MDM2/4-p53 pathways were abnormal in 89% (49 of 55) of cases. Simultaneous abnormalities of both pathways occurred in 84% (46 of 55) samples. The phosphoinositide 3-kinase pathway was altered in 71% (39 of 55) GBMs either by deletion of PTEN or amplification of epidermal growth factor receptor and/or vascular endothelial growth factor receptor/platelet-derived growth factor receptor α. Deletion of chromosome 6q26-27 often occurred (16 of 55 samples). The minimum common deleted region included PARK2, PACRG, QKI, and PDE10A genes. Further reverse transcription Q-PCR studies showed that PARK2 expression was decreased in another collection of GBMs at a frequency of 61% (34 of 56) of samples. The 1p36.23 region was deleted in 35% (19 of 55) of samples. Notably, three samples had homozygous deletion encompassing this site. Also, a novel internal deletion of a putative tumor suppressor gene, LRP1B, was discovered causing an aberrant protein.AUPDs occurred in 58% (32 of 55) of the GBM samples and five of six GBM cell lines. A common AUPD was found at chromosome 17p13.3-12 (included p53 gene) in 13 of 61 samples and cell lines. Single-strand conformational polymorphism and nucleotide sequencing showed that 9 of 13 of these samples had homozygous p53 mutations, suggesting that mitotic recombination duplicated the abnormal p53 gene, probably providing a growth advantage to these cells. A significantly shortened survival time was found in patients with 13q14 (RB) deletion or 17p13.1 (p53) deletion/AUPD. Taken together, these results suggest that this technique is a rapid, robust, and inexpensive method to profile genome-wide abnormalities in GBM. (Mol Cancer Res 2009;7(5):665-77)

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Section: Discussionmentioning

confidence: 89%

“…The short arm of chromosome 1 at 1p36 is frequently deleted in hematopoietic malignancies (34,35), epithelial cancers (36,37), and neural-related cancers, including neuroblastomas (38), meningiomas (39), and gliomas (40). Allelic loss at 1p has been reported in 20% to 30% of astrocytomas.…”

Section: Discussionmentioning

confidence: 99%

High-Resolution Genomic Copy Number Profiling of Glioblastoma Multiforme by Single Nucleotide Polymorphism DNA Microarray

Ding

Ogawa

Kawamata

et al. 2009

Molecular Cancer Research

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“…MAR and loop DNA fractions were labeled with Cy3-and Cy5-labeled dCTPs (Amersham Biosciences) using random prime labeling (Bioprime DNA Labeling System, Invitrogen) as described previously (Mulholland et al 2006). Unincorporated nucleotides were removed from the labeled DNA using Micro-spin G50 columns.…”

Section: Array Hybridizationmentioning

confidence: 99%

Reconfiguration of genomic anchors upon transcriptional activation of the human major histocompatibility complex

et al. 2008

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The folding of chromatin into topologically constrained loop domains is essential for genomic function. We have identified genomic anchors that define the organization of chromatin loop domains across the human major histocompatibility complex (MHC). This locus contains critical genes for immunity and is associated with more diseases than any other region of the genome. Classical MHC genes are expressed in a cell type-specific pattern and can be induced by cytokines such as interferon-gamma (IFNG). Transcriptional activation of the MHC was associated with a reconfiguration of chromatin architecture resulting from the formation of additional genomic anchors. These findings suggest that the dynamic arrangement of genomic anchors and loops plays a role in transcriptional regulation.

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“…The Cancer Genome Atlas Project (TCGA) (The Cancer Genome Atlas Research Network 2008) has compiled a large collection of highresolution genomic data from clinically annotated tumor samples, providing an unprecedented framework for the rapid discovery of novel cancer genes guided by cancer gene alterations across multiple dimensions of the genome. Here, in the course of conducting a functional genomic screen for p53 targets and mining the TCGA glioblastoma multiforme (GBM) data set and others (Mulholland et al 2006;Wiedemeyer et al 2008;Yin et al 2009), we identified Quaking (QKI) as a potential tumor suppressor gene that is frequently deleted in GBM. The potential importance of QKI in GBM pathogenesis is further elevated by its direct regulation by the TP53 tumor suppressor, the most commonly mutated gene in primary GBM .…”

mentioning

confidence: 99%

STAR RNA-binding protein Quaking suppresses cancer via stabilization of specific miRNA

et al. 2012

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Multidimensional cancer genome analysis and validation has defined Quaking (QKI), a member of the signal transduction and activation of RNA (STAR) family of RNA-binding proteins, as a novel glioblastoma multiforme (GBM) tumor suppressor. Here, we establish that p53 directly regulates QKI gene expression, and QKI protein associates with and leads to the stabilization of miR-20a; miR-20a, in turn, regulates TGFβR2 and the TGFβ signaling network. This pathway circuitry is substantiated by in silico epistasis analysis of its components in the human GBM TCGA (The Cancer Genome Atlas Project) collection and by their gain- and loss-of-function interactions in in vitro and in vivo complementation studies. This p53–QKI–miR-20a–TGFβ pathway expands our understanding of the p53 tumor suppression network in cancer and reveals a novel tumor suppression mechanism involving regulation of specific cancer-relevant microRNAs.

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Genomic Profiling Identifies Discrete Deletions Associated with Translocations in Glioblastoma Multiforme

Cited by 60 publications

References 36 publications

High-Resolution Genomic Copy Number Profiling of Glioblastoma Multiforme by Single Nucleotide Polymorphism DNA Microarray

High-Resolution Genomic Copy Number Profiling of Glioblastoma Multiforme by Single Nucleotide Polymorphism DNA Microarray

Reconfiguration of genomic anchors upon transcriptional activation of the human major histocompatibility complex

STAR RNA-binding protein Quaking suppresses cancer via stabilization of specific miRNA

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