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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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TACC3 is the predominant gene upregulated in 4p16.3 and correlates with Aurora kinase expression.SAGE of (A) TACC3 and FGFR3 and (B) Aurora kinases, AURKA, AURKB, and AURKC in normal brain (n = 2) and glioblastoma (n = 16) samples (data adapted from [5]). (C) Gene expression of TACC and Aurora kinase family members using the TCGA glioblastoma expression data set (n = 266) indicates correlation between TACC3 and AURKA (correlation coefficient = 0.76) and between TACC3 and AURKB (correlation coefficient = 0.70). Red indicates high gene expression level and green indicates low gene expression level.
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Figure 6: TACC3 is the predominant gene upregulated in 4p16.3 and correlates with Aurora kinase expression.SAGE of (A) TACC3 and FGFR3 and (B) Aurora kinases, AURKA, AURKB, and AURKC in normal brain (n = 2) and glioblastoma (n = 16) samples (data adapted from [5]). (C) Gene expression of TACC and Aurora kinase family members using the TCGA glioblastoma expression data set (n = 266) indicates correlation between TACC3 and AURKA (correlation coefficient = 0.76) and between TACC3 and AURKB (correlation coefficient = 0.70). Red indicates high gene expression level and green indicates low gene expression level.

Mentions: Focal gains on 4p16.3 were also frequently identified in a subset of glioblastomas (Figure 5A). We mapped the 4p16 duplications in a data set of 430 glioblastomas. The gains clustered in a minimal gained region centered on 4p16.3 from 1.5 to 2.0Mb (Figure 5B), containing SLBP, TMEM129, TACC3, FGFR3 and LETM1, of which TACC3 most commonly displayed gain of copy number. A Q-PCR analysis of an independent panel of glioblastoma samples detected genomic duplications of TACC3 in 5 out of 101 samples. In addition, compared with its adjacent genes, SLBP, TMEM129 and FGFR3 at 4p16.3, we found that TACC3 displayed a predominant overexpression pattern in glioblastomas (Figure 6A, S1 D).


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)

TACC3 is the predominant gene upregulated in 4p16.3 and correlates with Aurora kinase expression.SAGE of (A) TACC3 and FGFR3 and (B) Aurora kinases, AURKA, AURKB, and AURKC in normal brain (n = 2) and glioblastoma (n = 16) samples (data adapted from [5]). (C) Gene expression of TACC and Aurora kinase family members using the TCGA glioblastoma expression data set (n = 266) indicates correlation between TACC3 and AURKA (correlation coefficient = 0.76) and between TACC3 and AURKB (correlation coefficient = 0.70). Red indicates high gene expression level and green indicates low gene expression level.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: TACC3 is the predominant gene upregulated in 4p16.3 and correlates with Aurora kinase expression.SAGE of (A) TACC3 and FGFR3 and (B) Aurora kinases, AURKA, AURKB, and AURKC in normal brain (n = 2) and glioblastoma (n = 16) samples (data adapted from [5]). (C) Gene expression of TACC and Aurora kinase family members using the TCGA glioblastoma expression data set (n = 266) indicates correlation between TACC3 and AURKA (correlation coefficient = 0.76) and between TACC3 and AURKB (correlation coefficient = 0.70). Red indicates high gene expression level and green indicates low gene expression level.
Mentions: Focal gains on 4p16.3 were also frequently identified in a subset of glioblastomas (Figure 5A). We mapped the 4p16 duplications in a data set of 430 glioblastomas. The gains clustered in a minimal gained region centered on 4p16.3 from 1.5 to 2.0Mb (Figure 5B), containing SLBP, TMEM129, TACC3, FGFR3 and LETM1, of which TACC3 most commonly displayed gain of copy number. A Q-PCR analysis of an independent panel of glioblastoma samples detected genomic duplications of TACC3 in 5 out of 101 samples. In addition, compared with its adjacent genes, SLBP, TMEM129 and FGFR3 at 4p16.3, we found that TACC3 displayed a predominant overexpression pattern in glioblastomas (Figure 6A, S1 D).

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