Characterization of the amplicon on chromosomal segment 4q12 in glioblastoma multiforme

Holtkamp, Nikola; Ziegenhagen, Nicolas; Malzer, Elke; Hartmann, Christian; Giese, Alf; Deimling, Andreas von

doi:10.1215/15228517-2007-009

Cited by 51 publications

(55 citation statements)

References 16 publications

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“…It has been suggested that the MDM4 gene is the main amplification target in this amplicon (Riemenschneider et al, 2003) although it is not always coamplified in gliomas with hCNA of 1q32 [this study and see, e.g., (Rickman et al, 2001)]. Because single amplicons may contain several causal genes (Holtkamp et al, 2007) and the observation that MDM4 is not always coamplified, the 1q32 amplicon may contain additional oncogenes.…”

Section: Integrated Genomic Profiling Identifies Rbbp5 As a Candidatementioning

confidence: 73%

Integrated genomic profiling identifies candidate genes implicated in glioma‐genesis and a novel LEO1‐SLC12A1 fusion gene

Bralten

Kloosterhof

Gravendeel

et al. 2010

Genes Chromosomes & Cancer

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We performed genotyping and exon-level expression profiling on 21 glioblastomas (GBMs) and 19 oligodendrogliomas (ODs) to identify genes involved in glioma initiation and/or progression. Low-copy number amplifications (2.5 < n < 7) and high-copy number amplifications (n > 7) were more frequently observed in GBMs; ODs generally have more heterozygous deletions per tumor. Four high-copy amplicons were identified in more than one sample and resulted in overexpression of the known oncogenes EGFR, MDM2, and CDK4. In the fourth amplicon, RBBP5, a member of the RB pathway, may act as a novel oncogene in GBMs. Not all hCNAs contain known genes, which may suggest that other transcriptional and/or regulatory elements are the target for amplification. Regions with most frequent allelic loss, both in ODs and GBMs, resulted in a reduced expression of known tumor suppressor genes. We identified a homozygous deletion spanning the Pragmin gene in one sample, but direct sequencing of all coding exons in 20 other glioma samples failed to detect additional genetic changes. Finally, we screened for fusion genes by identifying aberrant 5'-3' expression of genes that lie over regions of a copy number change. A fusion gene between exon 11 of LEO1 and exon 10 of SLC12A1 was identified. Our data show that integrated genomic profiling can identify genes involved in tumor initiation, and/or progression and can be used as an approach to identify novel fusion genes.

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Section: Integrated Genomic Profiling Identifies Rbbp5 As a Candidatementioning

confidence: 73%

Integrated genomic profiling identifies candidate genes implicated in glioma‐genesis and a novel LEO1‐SLC12A1 fusion gene

Bralten

Kloosterhof

Gravendeel

et al. 2010

Genes Chromosomes & Cancer

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show abstract

“…48 Collectively, the GBMX tumor panel provides a valuable resource with which to dissect the biology of the amplicons described herein, as it is becoming clearer that multiple genes encoded within amplicons play important roles in driving tumor biology. 49,50 This in turn may lead to the development of novel therapeutic agents and strategies for disease treatment.…”

Section: The Mrc Expression Signature In Gbmx Tumorsmentioning

confidence: 99%

Comparative analyses of gene copy number and mRNA expression in glioblastoma multiforme tumors and xenografts

et al. 2009

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Development of model systems that recapitulate the molecular heterogeneity observed among glioblastoma multiforme (GBM) tumors will expedite the testing of targeted molecular therapeutic strategies for GBM treatment. In this study, we profiled DNA copy number and mRNA expression in 21 independent GBM tumor lines maintained as subcutaneous xenografts (GBMX), and compared GBMX molecular signatures to those observed in GBM clinical specimens derived from the Cancer Genome Atlas (TCGA). The predominant copy number signature in both tumor groups was defined by chromosome-7 gain/chromosome-10 loss, a poor-prognosis genetic signature. We also observed, at frequencies similar to that detected in TCGA GBM tumors, genomic amplification and overexpression of known GBM oncogenes, such as EGFR, MDM2, CDK6, and MYCN, and novel genes, including NUP107, SLC35E3, MMP1, MMP13, and DDX1. The transcriptional signature of GBMX tumors, which was stable over multiple subcutaneous passages, was defined by overexpression of genes involved in M phase, DNA replication, and chromosome organization (MRC) and was highly similar to the poor-prognosis mitosis and cell-cycle module (MCM) in GBM. Assessment of gene expression in TCGA-derived GBMs revealed overexpression of MRC cancer genes AURKB, BIRC5, CCNB1, CCNB2, CDC2, CDK2, and FOXM1, which form a transcriptional network important for G2/M progression and/or checkpoint activation. Our study supports propagation of GBM tumors as subcutaneous xenografts as a useful approach for sustaining key molecular characteristics of patient tumors, and highlights therapeutic opportunities conferred by this GBMX tumor panel for testing targeted therapeutic strategies for GBM treatment.

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“…It was also reported that KIT and PDGFRA could be altered in ALM by gene amplification mechanisms of their 4p12 locus [18][19][20]. Besides these two oncogenes, this locus also harbors another important oncogene, KDR, also known as VEGFR2 (vascular endothelial growth factor receptor-2 gene) [21,22]. Importantly, many of the mutated molecules in ALM have emerged for therapeutic targets, such as BRAF, KIT/ PDGFR, and VEGFR2 [23][24][25].…”

Section: Introductionmentioning

confidence: 99%

Molecular profiling, including TERT promoter mutations, of acral lentiginous melanomas

et al. 2016

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Acral lentiginous melanoma (ALM) is the less common subtype with singular characterization. TERT (human telomerase reverse transcriptase) promoter mutations have being described as recurrent in melanomas and infrequent in ALM, but their real incidence and clinical relevance is unclear. The objectives of this study were to describe the prevalence of TERT promoter mutations in ALM, and correlate with the molecular profile of other drive genes and clinical features. Sixty-one samples from 48 patients with ALM were analyzed. After DNA isolation, the mutation profiles of the hotspot region of BRAF, NRAS, KIT, PDGFRA, and TERT genes were determined by PCR amplification followed by direct Sanger sequencing. KIT, PDGFRA, and VEGFR2 gene amplification was performed by quantitative PCR. Clinical information such as survival, clinical stage, and Breslow tumor classification were obtained from medical records. TERT promoter mutations were found in 9.3% of the cases, BRAF in 10.3%, NRAS in 7.5%, KIT in 20.7%, and PDGFRA in 14.8% of ALM. None of the cases showed KIT, PDGFRA, or VEGFR2 gene amplification. We found an association between KIT mutations and advanced Clark level (IV and V, P=0.043) and TERT promoter mutations with low mitotic index. No other significant associations were observed between mutation profile and patients' clinical features nor survival rates. Oncogenic TERT promoter mutations are present in a fraction of ALMs. No relevant associations were found between TERT mutation status and clinical/molecular features nor survival. Mutations of KIT and PDGFRA are the most common genetic alterations, and they can be therapeutic targets for these patients.

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Characterization of the amplicon on chromosomal segment 4q12 in glioblastoma multiforme

Cited by 51 publications

References 16 publications

Integrated genomic profiling identifies candidate genes implicated in glioma‐genesis and a novel LEO1‐SLC12A1 fusion gene

Integrated genomic profiling identifies candidate genes implicated in glioma‐genesis and a novel LEO1‐SLC12A1 fusion gene

Comparative analyses of gene copy number and mRNA expression in glioblastoma multiforme tumors and xenografts

Molecular profiling, including TERT promoter mutations, of acral lentiginous melanomas

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