Identification of novel candidate target genes in amplicons of Glioblastoma multiforme tumors detected by expression and CGH microarray profiling View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2006-09-26

AUTHORS

Yolanda Ruano, Manuela Mollejo, Teresa Ribalta, Concepción Fiaño, Francisca I Camacho, Elena Gómez, Angel Rodríguez de Lope, Jose-Luis Hernández-Moneo, Pedro Martínez, Bárbara Meléndez

ABSTRACT

BACKGROUND: Conventional cytogenetic and comparative genomic hybridization (CGH) studies in brain malignancies have shown that glioblastoma multiforme (GBM) is characterized by complex structural and numerical alterations. However, the limited resolution of these techniques has precluded the precise identification of detailed specific gene copy number alterations. RESULTS: We performed a genome-wide survey of gene copy number changes in 20 primary GBMs by CGH on cDNA microarrays. A novel amplicon at 4p15, and previously uncharacterized amplicons at 13q32-34 and 1q32 were detected and are analyzed here. These amplicons contained amplified genes not previously reported. Other amplified regions containing well-known oncogenes in GBMs were also detected at 7p12 (EGFR), 7q21 (CDK6), 4q12 (PDGFRA), and 12q13-15 (MDM2 and CDK4). In order to identify the putative target genes of the amplifications, and to determine the changes in gene expression levels associated with copy number change events, we carried out parallel gene expression profiling analyses using the same cDNA microarrays. We detected overexpression of the novel amplified genes SLA/LP and STIM2 (4p15), and TNFSF13B and COL4A2 (13q32-34). Some of the candidate target genes of amplification (EGFR, CDK6, MDM2, CDK4, and TNFSF13B) were tested in an independent set of 111 primary GBMs by using FISH and immunohistological assays. The novel candidate 13q-amplification target TNFSF13B was amplified in 8% of the tumors, and showed protein expression in 20% of the GBMs. CONCLUSION: This high-resolution analysis allowed us to propose novel candidate target genes such as STIM2 at 4p15, and TNFSF13B or COL4A2 at 13q32-34 that could potentially contribute to the pathogenesis of these tumors and which would require futher investigations. We showed that overexpression of the amplified genes could be attributable to gene dosage and speculate that deregulation of those genes could be important in the development and progression of GBM. Our findings highlight the important influence in GBM of signaling pathways such as the PI3K/AKT, consistent with the invasive features of this tumor. More... »

PAGES

39-39

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/1476-4598-5-39

DOI

http://dx.doi.org/10.1186/1476-4598-5-39

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1029848156

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/17002787


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35 schema:description BACKGROUND: Conventional cytogenetic and comparative genomic hybridization (CGH) studies in brain malignancies have shown that glioblastoma multiforme (GBM) is characterized by complex structural and numerical alterations. However, the limited resolution of these techniques has precluded the precise identification of detailed specific gene copy number alterations. RESULTS: We performed a genome-wide survey of gene copy number changes in 20 primary GBMs by CGH on cDNA microarrays. A novel amplicon at 4p15, and previously uncharacterized amplicons at 13q32-34 and 1q32 were detected and are analyzed here. These amplicons contained amplified genes not previously reported. Other amplified regions containing well-known oncogenes in GBMs were also detected at 7p12 (EGFR), 7q21 (CDK6), 4q12 (PDGFRA), and 12q13-15 (MDM2 and CDK4). In order to identify the putative target genes of the amplifications, and to determine the changes in gene expression levels associated with copy number change events, we carried out parallel gene expression profiling analyses using the same cDNA microarrays. We detected overexpression of the novel amplified genes SLA/LP and STIM2 (4p15), and TNFSF13B and COL4A2 (13q32-34). Some of the candidate target genes of amplification (EGFR, CDK6, MDM2, CDK4, and TNFSF13B) were tested in an independent set of 111 primary GBMs by using FISH and immunohistological assays. The novel candidate 13q-amplification target TNFSF13B was amplified in 8% of the tumors, and showed protein expression in 20% of the GBMs. CONCLUSION: This high-resolution analysis allowed us to propose novel candidate target genes such as STIM2 at 4p15, and TNFSF13B or COL4A2 at 13q32-34 that could potentially contribute to the pathogenesis of these tumors and which would require futher investigations. We showed that overexpression of the amplified genes could be attributable to gene dosage and speculate that deregulation of those genes could be important in the development and progression of GBM. Our findings highlight the important influence in GBM of signaling pathways such as the PI3K/AKT, consistent with the invasive features of this tumor.
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42 schema:keywords Akt
43 CGH
44 CGH microarray profiling
45 COL4A2
46 LP
47 PI3K/Akt
48 SLA/LP
49 STIM2
50 TNFSF13B
51 alterations
52 amplicons
53 amplification
54 analysis
55 assays
56 brain malignancies
57 cDNA microarray
58 candidate 13q-amplification target
59 candidate target genes
60 change events
61 changes
62 comparative genomic hybridization study
63 conclusion
64 copy number alterations
65 copy number change events
66 copy number changes
67 deregulation
68 detailed specific gene copy number alterations
69 development
70 dosage
71 events
72 expression
73 expression levels
74 features
75 findings
76 fish
77 futher investigation
78 gene copy number alterations
79 gene copy number changes
80 gene dosage
81 gene expression
82 gene expression levels
83 genes
84 genes SLA/LP
85 genome-wide survey
86 genomic hybridization study
87 glioblastoma multiforme
88 glioblastoma multiforme tumors
89 high-resolution analysis
90 hybridization studies
91 identification
92 immunohistological assays
93 important influence
94 independent set
95 influence
96 invasive features
97 investigation
98 levels
99 limited resolution
100 malignancy
101 microarray profiling
102 microarrays
103 multiforme
104 multiforme tumors
105 novel amplicon
106 novel candidate 13q-amplification target
107 novel candidate target genes
108 number alterations
109 number change events
110 number changes
111 numerical alterations
112 oncogene
113 order
114 overexpression
115 parallel gene expression
116 pathogenesis
117 pathway
118 precise identification
119 primary glioblastoma multiforme
120 profiling
121 progression
122 progression of GBM
123 protein expression
124 putative target genes
125 region
126 resolution
127 same cDNA microarrays
128 set
129 specific gene copy number alterations
130 study
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132 target
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134 technique
135 tumors
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