title: Integrated genomic profiling identifies candidate genes implicated in glioma-genesis and a novel LEO1-SLC12A1 fusion gene.
abstract: 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.
authors.affiliation: Department of Neurology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Linda B C
authors.initials: LB
authors.lastname: Bralten
authors.forename: Nanne K
authors.initials: NK
authors.lastname: Kloosterhof
authors.forename: Lonneke A M
authors.initials: LA
authors.lastname: Gravendeel
authors.forename: Andrea
authors.initials: A
authors.lastname: Sacchetti
authors.forename: Elza J
authors.initials: EJ
authors.lastname: Duijm
authors.forename: Johan M
authors.initials: JM
authors.lastname: Kros
authors.forename: Martin J
authors.initials: MJ
authors.lastname: van den Bent
authors.forename: Casper C
authors.initials: CC
authors.lastname: Hoogenraad
authors.forename: Peter A E
authors.initials: PA
authors.lastname: Sillevis Smitt
authors.forename: Pim J
authors.initials: PJ
authors.lastname: French
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics*; D056915:DNA Copy Number Variations; D004268:DNA-Binding Proteins; D020869:Gene Expression Profiling / Q000379:methods; D016147:Genes, Tumor Suppressor; D005909:Glioblastoma / Q000235:genetics*; D006651:Histocytochemistry; D006801:Humans; D009687:Nuclear Proteins; D009837:Oligodendroglioma / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics*; D064466:Solute Carrier Family 12, Member 1; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic
chemical_list: D004268:DNA-Binding Proteins; C506154:LEO1 protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; C470552:RBBP5 protein, human; C578714:SLC12A1 protein, human; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D014157:Transcription Factors