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Integrated genomic analyses identify ERRFI1 and TACC3 as glioblastoma-targeted genes.

Duncan CG, Killela PJ, Payne CA, Lampson B, Chen WC, Liu J, Solomon D, Waldman T, Towers AJ, Gregory SG, McDonald KL, McLendon RE, Bigner DD, Yan H - Oncotarget (2010)

Bottom Line: From this study, we identified recurrent focal copy number alterations in 1p36.23 and 4p16.3.Specifically, we identify EGFR negative regulator, ERRFI1, within the minimal region of deletion in 1p36.23.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.

View Article: PubMed Central - PubMed

Affiliation: The Preston Robert Tisch Brain Tumor Center, The Pediatric Brain Tumor Foundation, The Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.

ABSTRACT
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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Focal high copy number gains and homozygous deletions in glioblastomas.Copy number analysis using DK and Illumina BeadChips revealed gains (indicated by green) and losses (indicated by red) spanning the genome of glioblastomas. (A) Glioblastoma copy number karyotype generated utilizing Nexus Copy Number Professional Software (BioDiscovery Inc.). The most common regions for (B) focal deletion and (C) focal gain of copy number in 111 glioblastomas. Loci are identified with reported tumor suppressor genes and oncogenes if available.
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Figure 1: Focal high copy number gains and homozygous deletions in glioblastomas.Copy number analysis using DK and Illumina BeadChips revealed gains (indicated by green) and losses (indicated by red) spanning the genome of glioblastomas. (A) Glioblastoma copy number karyotype generated utilizing Nexus Copy Number Professional Software (BioDiscovery Inc.). The most common regions for (B) focal deletion and (C) focal gain of copy number in 111 glioblastomas. Loci are identified with reported tumor suppressor genes and oncogenes if available.

Mentions: Of the genomic copy number profiles from a total of 111 glioblastoma samples assessed by DK or Illumina BeadChips, we identified a high degree of heterogeneity and copy number instability across the glioblastoma genomes (Figure 1A). Despite heterogeneity, we detected several regions which are recurrently gained or lost in glioblastomas (Figure 1B, C). The two most prevalent focal amplifications were the EGFR and CDK4 loci, occurring in 42% and 12% of all cases, respectively. The two most prevalent focal deletions were the CDKN2A/B and 1p36 loci, occurring in 40% and 9% of all samples, respectively. Additionally, we detected multiple intragenic homozygous deletions within large genes, including LRP1B, WWOX, and A2BP1.


Integrated genomic analyses identify ERRFI1 and TACC3 as glioblastoma-targeted genes.

Duncan CG, Killela PJ, Payne CA, Lampson B, Chen WC, Liu J, Solomon D, Waldman T, Towers AJ, Gregory SG, McDonald KL, McLendon RE, Bigner DD, Yan H - Oncotarget (2010)

Focal high copy number gains and homozygous deletions in glioblastomas.Copy number analysis using DK and Illumina BeadChips revealed gains (indicated by green) and losses (indicated by red) spanning the genome of glioblastomas. (A) Glioblastoma copy number karyotype generated utilizing Nexus Copy Number Professional Software (BioDiscovery Inc.). The most common regions for (B) focal deletion and (C) focal gain of copy number in 111 glioblastomas. Loci are identified with reported tumor suppressor genes and oncogenes if available.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2992381&req=5

Figure 1: Focal high copy number gains and homozygous deletions in glioblastomas.Copy number analysis using DK and Illumina BeadChips revealed gains (indicated by green) and losses (indicated by red) spanning the genome of glioblastomas. (A) Glioblastoma copy number karyotype generated utilizing Nexus Copy Number Professional Software (BioDiscovery Inc.). The most common regions for (B) focal deletion and (C) focal gain of copy number in 111 glioblastomas. Loci are identified with reported tumor suppressor genes and oncogenes if available.
Mentions: Of the genomic copy number profiles from a total of 111 glioblastoma samples assessed by DK or Illumina BeadChips, we identified a high degree of heterogeneity and copy number instability across the glioblastoma genomes (Figure 1A). Despite heterogeneity, we detected several regions which are recurrently gained or lost in glioblastomas (Figure 1B, C). The two most prevalent focal amplifications were the EGFR and CDK4 loci, occurring in 42% and 12% of all cases, respectively. The two most prevalent focal deletions were the CDKN2A/B and 1p36 loci, occurring in 40% and 9% of all samples, respectively. Additionally, we detected multiple intragenic homozygous deletions within large genes, including LRP1B, WWOX, and A2BP1.

Bottom Line: From this study, we identified recurrent focal copy number alterations in 1p36.23 and 4p16.3.Specifically, we identify EGFR negative regulator, ERRFI1, within the minimal region of deletion in 1p36.23.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.

View Article: PubMed Central - PubMed

Affiliation: The Preston Robert Tisch Brain Tumor Center, The Pediatric Brain Tumor Foundation, The Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus