Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0017636 (glioblastoma)
18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The PTEN gene, recently identified on chromosome 10q23, has been proposed to be a candidate tumor suppressor gene inactivated in multiple cancers including glial tumors. We investigated 47 glioblastomas (GBM), 14 anaplastic astrocytomas (AA), 6 non-pilocytic low-grade astrocytomas (LGA), 21 low-grade and anaplastic oligodendrogliomas (O) and oligoastrocytomas (OA), and 3 ependymomas (E) for mutation of the PTEN gene using denaturing gradient gel electrophoresis (DGGE) followed by DNA sequencing. These tumors have been previously screened for loss of heterozygosity (LOH) on chromosome 10q, p53 mutations and EGFR amplification. Overall, PTEN mutations, detected in 14 of 91 tumors, were present in 13 of 47 GBM and 1 of 14 AA. In contrast, mutations were absent in other glioma subtypes (0/30). In all informative cases, PTEN mutations occurred in tumors showing LOH on chromosome 10q, confirming the inactivation of this gene by a 2-hit mechanism. No correlation was observed between the presence of PTEN mutation and p53 mutation and EGFR amplification. Our results indicate that biallelic PTEN inactivation plays an important role in the pathogenesis of high-grade astrocytomas as a late event. Moreover, they suggest that PTEN alterations are equally involved in the 2 glioblastoma pathways defined by the presence of EGFR amplification and p53 mutation. Finally, correlation analysis with clinical data did not show that PTEN mutation was linked to survival of the patients.
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PMID:Mutational analysis of the PTEN gene in gliomas: molecular and pathological correlations. 1009 47

We have constructed the first comprehensive microarray representing a human chromosome for analysis of DNA copy number variation. This chromosome 22 array covers 34.7 Mb, representing 1.1% of the genome, with an average resolution of 75 kb. To demonstrate the utility of the array, we have applied it to profile acral melanoma, dermatofibrosarcoma, DiGeorge syndrome and neurofibromatosis 2. We accurately diagnosed homozygous/heterozygous deletions, amplifications/gains, IGLV/IGLC locus instability, and breakpoints of an imbalanced translocation. We further identified the 14-3-3 eta isoform as a candidate tumor suppressor in glioblastoma. Two significant methodological advances in array construction were also developed and validated. These include a strictly sequence defined, repeat-free, and non-redundant strategy for array preparation. This approach allows an increase in array resolution and analysis of any locus; disregarding common repeats, genomic clone availability and sequence redundancy. In addition, we report that the application of phi29 DNA polymerase is advantageous in microarray preparation. A broad spectrum of issues in medical research and diagnostics can be approached using the array. This well annotated and gene-rich autosome contains numerous uncharacterized disease genes. It is therefore crucial to associate these genes to specific 22q-related conditions and this array will be instrumental towards this goal. Furthermore, comprehensive epigenetic profiling of 22q-located genes and high-resolution analysis of replication timing across the entire chromosome can be studied using our array.
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PMID:A full-coverage, high-resolution human chromosome 22 genomic microarray for clinical and research applications. 1244 6

We have identified an 85 kb BAC clone, 346J21, that carries a cell senescence gene (SEN16), previously mapped to 16q24.3. Transfer and retention of 346J21 in breast cancer cell lines leads to growth arrest after 8-10 cell doublings, accompanied by the appearance of characteristic senescent cell morphology and senescence-associated acid beta-galactosidase activity. Loss of transferred BAC results in reversion to the immortal growth phenotype of the parental cancer cell lines. BAC 346J21 restores senescence in the human breast cancer cell lines, MCF.7 and MDA-MB468, and the rat mammary tumor cell line LA7, but not in the human glioblastoma cell line T98G. We postulate that inactivation of both copies of SEN16 is required for the immortalization of breast epithelial cells at an early stage of tumorigenesis. Positional mapping of 346J21 shows that SEN16 is distinct from other candidate tumor suppressor genes reported at 16q24.
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PMID:Functional identification of a BAC clone from 16q24 carrying a senescence gene SEN16 for breast cancer cells. 1555 27

Inhibitor of growth 4 (ING4) is a candidate tumor suppressor that plays a major role in gene regulation, cell cycle control, apoptosis, and angiogenesis. ING4 expression is down-regulated in glioblastoma cells and head and neck squamous cell carcinoma. Here, we identified liprin alpha1/PPFIA1, a cytoplasmic protein necessary for focal adhesion formation and axon guidance, as a novel interacting protein with ING4. ING4 and liprin alpha1 colocalized at lamellipodia in the vicinity of vinculin. Overexpressed ING4 suppressed cell spreading and cell migration. In contrast, overexpressed liprin alpha1 enhanced cell spreading and cell migration. Knockdown of endogenous ING4 with RNA interference induced cell motility, whereas knockdown of endogenous liprin alpha1 suppressed cell motility. ING4 also suppressed cell motility that was enhanced by liprin alpha1. However, ING4 did not further suppress cell motility when liprin alpha1 was suppressed with RNA interference, suggesting a functional and mechanistic interdependence between these proteins. In addition to its nuclear functions, cytoplasmic ING4 interacts with liprin alpha1 to regulate cell migration and, with its known antiangiogenic function, may prevent invasion and metastasis.
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PMID:Inhibitor of growth 4 suppresses cell spreading and cell migration by interacting with a novel binding partner, liprin alpha1. 1736 73

The N-myc downstream-regulated gene 2 (NDRG2) at 14q11.2 has been reported to be downregulated in glioblastoma, and NDRG2 overexpression represses glioblastoma cell proliferation in vitro (Deng et al., Int J Cancer 2003;106;342-7). To further address the role of NDRG2 as a candidate tumor suppressor in human gliomas, we analyzed 67 astrocytic tumors (10 diffuse astrocytomas, 11 anaplastic astrocytomas, 34 primary glioblastomas and 12 secondary glioblastomas) for NDRG2 gene mutation, promoter methylation and expression at the mRNA and protein levels. Using real-time reverse transcription PCR analysis, we found decreased NDRG2 mRNA levels in primary glioblastomas as compared to diffuse and anaplastic astrocytomas. Similarly, immunohistochemistry revealed low or absent NDRG2 protein expression in primary glioblastomas. Mutational analysis of the entire NDRG2 coding sequence did not reveal any tumor-associated DNA sequence alterations. However, sequencing of sodium bisulfite-modified DNA identified hypermethylation of the NDRG2 promoter region in 21 of 34 primary glioblastomas (62%). Moreover, NDRG2 promoter hypermethylation was associated with decreased NDRG2 mRNA expression. In contrast to primary glioblastomas, NDRG2 promoter hypermethylation was detected in only 1 of 11 anaplastic astrocytomas (9%) and was absent in 10 diffuse astrocytomas and 12 secondary glioblastomas. Taken together, our data support NDRG2 as a candidate tumor suppressor gene that is epigenetically silenced in the majority of primary glioblastomas, but not in lower grade astrocytomas and secondary glioblastomas.
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PMID:Frequent promoter hypermethylation and transcriptional downregulation of the NDRG2 gene at 14q11.2 in primary glioblastoma. 1870 45

NDRG2 (N-myc downstream-regulated gene 2) is a candidate tumor suppressor implicated in control of glioblastoma proliferation and dendritic cell differentiation. The microphthalmia-associated transcription factor (Mitf) plays a crucial role in the melanocyte lineage and in melanoma by controlling survival, differentiation, cell cycle entry and exit, and melanoma metastasis. Identifying upstream regulators of Mitf expression, therefore, remains a key issue. In this study, we aimed to assess whether the candidate tumor suppressor NDRG2 can modulate Mitf expression. Here, we show that NDRG2 acts to prevent cAMP and beta-catenin-mediated activation of the Mitf promoter, thereby blocking melanogenesis via the downstream Mitf target genes Tyrosinase, Tyrp1 and Dct. The data suggest that NDRG2 impairs melanogenesis by interfering with both the TCF/beta-catenin and cAMP/CREB pathways that are known to stimulate Mitf expression in melanocytes and have major implications for the role of NDRG2 in pigmentation and melanoma progression. Taken together, the results not only identify NDRG2 as a novel regulator of pigmentation, but also potentially a key factor in regulating melanoma progression via Mitf.
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PMID:NDRG2 gene expression in B16F10 melanoma cells restrains melanogenesis via inhibition of Mitf expression. 1906 70

Glioblastomas (GBs) are malignant CNS tumors often associated with devastating symptoms. Patients with GB have a very poor prognosis, and despite treatment, most of them die within 12 months from diagnosis. Several pathways, such as the RAS, tumor protein 53 (TP53), and phosphoinositide kinase 3 (PIK3) pathways, as well as the cell cycle control pathway, have been identified to be disrupted in this tumor. However, emerging data suggest that these aberrations represent only a fraction of the genetic changes involved in gliomagenesis. In this study, we have applied a 32K clone-based genomic array, covering 99% of the current assembly of the human genome, to the detailed genetic profiling of a set of 78 GBs. Complex patterns of aberrations, including high and narrow copy number amplicons, as well as a number of homozygously deleted loci, were identified. Amplicons that varied both in number (three on average) and in size (1.4 Mb on average) were frequently detected (81% of the samples). The loci encompassed not only previously reported oncogenes (EGFR, PDGFRA, MDM2, and CDK4) but also numerous novel oncogenes as GRB10, MKLN1, PPARGC1A, HGF, NAV3, CNTN1, SYT1, and ADAMTSL3. BNC2, PTPLAD2, and PTPRE, on the other hand, represent novel candidate tumor suppressor genes encompassed within homozygously deleted loci. Many of these genes are already linked to several forms of cancer; others represent new candidate genes that may serve as prognostic markers or even as therapeutic targets in the future. The large individual variation observed between the samples demonstrates the underlying complexity of the disease and strengthens the demand for an individualized therapy based on the genetic profile of the patient.
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PMID:Characterization of novel and complex genomic aberrations in glioblastoma using a 32K BAC array. 1930 58

The glioblastoma genome displays remarkable chromosomal aberrations, which harbor critical glioblastoma-specific genes contributing to several oncogenetic pathways. To identify glioblastoma-targeted genes, we completed a multifaceted genome-wide analysis to characterize the most significant aberrations of DNA content occurring in glioblastomas. We performed copy number analysis of 111 glioblastomas by Digital Karyotyping and Illumina BeadChip assays and validated our findings using data from the TCGA (The Cancer Genome Atlas) glioblastoma project. From this study, we identified recurrent focal copy number alterations in 1p36.23 and 4p16.3. Expression analyses of genes located in the two regions revealed genes which are dysregulated in glioblastomas. Specifically, we identify EGFR negative regulator, ERRFI1, within the minimal region of deletion in 1p36.23. In glioblastoma cells with a focal deletion of the ERRFI1 locus, restoration of ERRFI1 expression slowed cell migration. Furthermore, we demonstrate that TACC3, an Aurora-A kinase substrate, on 4p16.3, displays gain of copy number, is overexpressed in a glioma-grade-specific pattern, and correlates with Aurora kinase overexpression in glioblastomas. Our multifaceted genomic evaluation of glioblastoma establishes ERRFI1 as a potential candidate tumor suppressor gene and TACC3 as a potential oncogene, and provides insight on targets for oncogenic pathway-based therapy.
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PMID:Integrated genomic analyses identify ERRFI1 and TACC3 as glioblastoma-targeted genes. 2130 75

RRP22 (Ras-related protein on chromosome 22) has been suggested as a candidate tumor suppressor in human cancers. Investigating a panel of 70 human gliomas, we found a frequent decrease in the RRP22 mRNA expression levels (67%), preferentially in high-grade gliomas [World Health Organization (WHO) grades III and IV] as compared with low-grade gliomas (WHO grade II). Moreover, reduced RRP22 mRNA expression was associated with shorter overall survival in 180 glioblastoma patients included in the National Institutes of Health Repository for Molecular Brain Neoplasia Data (NIH REMBRANDT) database. Decreased RRP22 expression levels were in part explained by 5'-CpG island hypermethylation and increased by the treatment with the demethylating agent 5-aza-2'-deoxycytidine in glioblastoma cell lines. In addition, the in vitro treatment with the histone deacetylase inhibitor trichostatin A alone resulted in RRP22 reexpression as well as a significant increase in the levels of RRP22 promoter DNA bound to pan-acetylated histone H3 and H4. Moreover, in primary human glioblastomas, we observed an increase of H3K9me3-bound and a decrease of pan-Ac-H3-bound RRP22 in comparison with non-neoplastic brain tissue, consistent with a heterochromatinization of the RRP22 promoter. Taken together, our findings demonstrate that both 5'-CpG island hypermethylation and histone modifications contribute to the frequent and prognostically unfavorable transcriptional downregulation of RRP22 in malignant gliomas.
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PMID:DNA hypermethylation and histone modifications downregulate the candidate tumor suppressor gene RRP22 on 22q12 in human gliomas. 2163 28

Gene expression-based prediction of genomic copy number aberrations in the chromosomal region 12q13 to 12q15 that is flanked by MDM2 and CDK4 identified Wnt inhibitory factor 1 (WIF1) as a candidate tumor suppressor gene in glioblastoma. WIF1 encodes a secreted Wnt antagonist and was strongly downregulated in most glioblastomas as compared with normal brain, implying deregulation of Wnt signaling, which is associated with cancer. WIF1 silencing was mediated by deletion (7/69, 10%) or epigenetic silencing by promoter hypermethylation (29/110, 26%). Co-amplification of MDM2 and CDK4 that is present in 10% of glioblastomas was associated in most cases with deletion of the whole genomic region enclosed, including the WIF1 locus. This interesting pathogenetic constellation targets the RB and p53 tumor suppressor pathways in tandem, while simultaneously activating oncogenic Wnt signaling. Ectopic expression of WIF1 in glioblastoma cell lines revealed a dose-dependent decrease of Wnt pathway activity. Furthermore, WIF1 expression inhibited cell proliferation in vitro, reduced anchorage-independent growth in soft agar, and completely abolished tumorigenicity in vivo. Interestingly, WIF1 overexpression in glioblastoma cells induced a senescence-like phenotype that was dose dependent. These results provide evidence that WIF1 has tumor suppressing properties. Downregulation of WIF1 in 75% of glioblastomas indicates frequent involvement of aberrant Wnt signaling and, hence, may render glioblastomas sensitive to inhibitors of Wnt signaling, potentially by diverting the tumor cells into a senescence-like state.
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PMID:The Wnt inhibitory factor 1 (WIF1) is targeted in glioblastoma and has a tumor suppressing function potentially by induction of senescence. 2164 72


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