A study of loss of heterozygosity at 70 loci in anaplastic astrocytoma and glioblastoma multiforme with implications for tumor evolution

Wooten, Eric C.; Fults, Dan; Duggirala, Ravindrannath; Williams, Kenneth S.; P.Kyritsis, Athanassias; Bondy, Melissa L.; Levin, Victor A.; O’Connell, P.

doi:10.1215/s1522851798000283

Cited by 6 publications

(6 citation statements)

References 19 publications

(22 reference statements)

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“…The long arm of chromosome 14 has been reported as a common region of nonrandom allelic losses in glioblastomas. The reported frequency of loss of heterozygosity on 14q in gliomas varies from about 20% up to 50% of cases 27–29. In our glioblastoma series, we detected loss of heterozygosity on 14q in only 3 of 36 tumors (8%).…”

Section: Discussioncontrasting

confidence: 43%

Frequent promoter hypermethylation and transcriptional downregulation of the NDRG2 gene at 14q11.2 in primary glioblastoma

Tepel

Roerig

Wolter

et al. 2008

Intl Journal of Cancer

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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 bisulfitemodified 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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Section: Discussioncontrasting

confidence: 43%

Frequent promoter hypermethylation and transcriptional downregulation of the NDRG2 gene at 14q11.2 in primary glioblastoma

Tepel

Roerig

Wolter

et al. 2008

Intl Journal of Cancer

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“…Loss of chromosomal material from 6q has been reported in fractions of cases in several glioma types. 11,22,26,43 Interestingly, in intracranial ependymoma, loss on chromosome arm 6q has been described as a particularly frequent genetic alteration, affecting 20% to 30% of tumors. 8,16,17,19,24,29 A candidate at 6q24.2 is the PLAGL1/ZAC1 gene, which encodes a zinc-finger transcription factor that induces apoptosis and cell cycle arrest, and has been reported to be deleted or epigenetically silenced in various solid cancers.…”

Section: Discussionmentioning

confidence: 99%

Angiocentric Glioma

Preusser¹,

Hoischen

Novak³

et al. 2007

American Journal of Surgical Pathology

108

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Angiocentric glioma has recently been described as a novel epilepsy associated tumor with distinct clinico-pathologic features. We report the clinical and pathologic findings in 8 additional cases of this rare tumor type and extend its characterization by genomic profiling. Almost all patients had a history of long-standing drug-resistant epilepsy. Cortico-subcortical tumors were located in the temporal and parietal lobes. Seizures began at 3 to 14 years of age and surgery was performed at 6 to 70 years. Histologically, the tumors were characterized by diffuse growth and prominent perivascular tumor cell arrangements with features of astrocytic/ependymal differentiation, but lacking neoplastic neuronal features. Necrosis and vascular proliferation were not observed and mitoses were sparse or absent. MIB-1 proliferation indices ranged from <1% to 5%. Immunohistochemically, all cases stained positively for glial fibrillary acidic protein, vimentin, protein S100B, variably for podoplanin, and showed epithelial membrane antigen-positive cytoplasmic dots. Electron microscopy showed ependymal characteristics in 2 of 3 cases investigated. An analysis of genomic imbalances by chromosomal comparative genomic hybridization revealed loss of chromosomal bands 6q24 to q25 as the only alteration in 1 of 8 cases. In 1 of 3 cases, a high-resolution screen by array-comparative genomic hybridization identified a copy number gain of 2 adjacent clones from chromosomal band 11p11.2 containing the protein-tyrosine phosphatase receptor type J (PTPRJ) gene. All patients are seizure free and without evidence of tumor recurrence at follow-up times ranging from 1/2 to 6.9 years. Our findings support 2 previous reports proposing that angiocentric glioma is a novel glial tumor entity of low-grade malignancy.

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“…One of these genes is PTEN, a gene on 10q23 which encodes a dual-specificity protein phosphatase [29]. Lower losses on chromosome 10 are seen in anaplastic astrocytoma indicating that loss of heterozygosity on chromosome 10 is a terminal genetic event associated with GBM [30]. Loss of heterozygosity on chromosome 10q has been found to be associated with reduced survival of GBM patients [9] and in a study of 25 cases of GBM in Indian patients was seen more frequently in older patients [31].…”

Section: Molecular and Metabolic Alterations In Gbm And Their Potementioning

confidence: 99%

Emerging Biomarkers in Glioblastoma

McNamara

Sahebjam

Mason

2013

Cancers

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Glioblastoma, the most common primary brain tumor, has few available therapies providing significant improvement in survival. Molecular signatures associated with tumor aggressiveness as well as with disease progression and their relation to differences in signaling pathways implicated in gliomagenesis have recently been described. A number of biomarkers which have potential in diagnosis, prognosis and prediction of response to therapy have been identified and along with imaging modalities could contribute to the clinical management of GBM. Molecular biomarkers including O(6)-methlyguanine-DNA-methyltransferase (MGMT) promoter and deoxyribonucleic acid (DNA) methylation, loss of heterozygosity (LOH) of chromosomes 1p and 19q, loss of heterozygosity 10q, isocitrate dehydrogenase (IDH) mutations, epidermal growth factor receptor (EGFR), epidermal growth factor, latrophilin, and 7 transmembrane domain-containing protein 1 on chromosome 1 (ELTD1), vascular endothelial growth factor (VEGF), tumor suppressor protein p53, phosphatase and tensin homolog (PTEN), p16INK4a gene, cytochrome c oxidase (CcO), phospholipid metabolites, telomerase messenger expression (hTERT messenger ribonucleic acid [mRNA]), microRNAs (miRNAs), cancer stem cell markers and imaging modalities as potential biomarkers are discussed. Inclusion of emerging biomarkers in prospective clinical trials is warranted in an effort for more effective personalized therapy in the future.

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A study of loss of heterozygosity at 70 loci in anaplastic astrocytoma and glioblastoma multiforme with implications for tumor evolution

Cited by 6 publications

References 19 publications

Frequent promoter hypermethylation and transcriptional downregulation of the NDRG2 gene at 14q11.2 in primary glioblastoma

Frequent promoter hypermethylation and transcriptional downregulation of the NDRG2 gene at 14q11.2 in primary glioblastoma

Angiocentric Glioma

Emerging Biomarkers in Glioblastoma

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