Integrated genomic analyses identify ERRFI1 and TACC3 as glioblastoma-targeted genes.
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.
The Preston Robert Tisch Brain Tumor Center, The Pediatric Brain Tumor Foundation, The Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
Christopher G
CG
Duncan
Patrick J
PJ
Killela
Cathy A
CA
Payne
Benjamin
B
Lampson
William C
WC
Chen
Jeff
J
Liu
David
D
Solomon
Todd
T
Waldman
Aaron J
AJ
Towers
Simon G
SG
Gregory
Kerrie L
KL
McDonald
Roger E
RE
McLendon
Darell D
DD
Bigner
Hai
H
Yan
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D056915:DNA Copy Number Variations; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D056726:Genetic Association Studies; D005909:Glioblastoma / Q000235:genetics*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009154:Mutation; D009857:Oncogenes; D016133:Polymerase Chain Reaction; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; C484017:ERRFI1 protein, human; D008869:Microtubule-Associated Proteins; C120551:TACC3 protein, human; D025521:Tumor Suppressor Proteins