title: Characterization of novel and complex genomic aberrations in glioblastoma using a 32K BAC array.
abstract: Glioblastomas (GBs) are malignant CNS tumors often associated with devastating symptoms. Patients with GB have a very poor prognosis, and despite treatment, most of them die within 12 months from diagnosis. Several pathways, such as the RAS, tumor protein 53 (TP53), and phosphoinositide kinase 3 (PIK3) pathways, as well as the cell cycle control pathway, have been identified to be disrupted in this tumor. However, emerging data suggest that these aberrations represent only a fraction of the genetic changes involved in gliomagenesis. In this study, we have applied a 32K clone-based genomic array, covering 99% of the current assembly of the human genome, to the detailed genetic profiling of a set of 78 GBs. Complex patterns of aberrations, including high and narrow copy number amplicons, as well as a number of homozygously deleted loci, were identified. Amplicons that varied both in number (three on average) and in size (1.4 Mb on average) were frequently detected (81% of the samples). The loci encompassed not only previously reported oncogenes (EGFR, PDGFRA, MDM2, and CDK4) but also numerous novel oncogenes as GRB10, MKLN1, PPARGC1A, HGF, NAV3, CNTN1, SYT1, and ADAMTSL3. BNC2, PTPLAD2, and PTPRE, on the other hand, represent novel candidate tumor suppressor genes encompassed within homozygously deleted loci. Many of these genes are already linked to several forms of cancer; others represent new candidate genes that may serve as prognostic markers or even as therapeutic targets in the future. The large individual variation observed between the samples demonstrates the underlying complexity of the disease and strengthens the demand for an individualized therapy based on the genetic profile of the patient.
authors.affiliation: Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, SE-75185 Uppsala, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Nord
authors.forename: Christian
authors.initials: C
authors.lastname: Hartmann
authors.forename: Robin
authors.initials: R
authors.lastname: Andersson
authors.forename: Uwe
authors.initials: U
authors.lastname: Menzel
authors.forename: Susan
authors.initials: S
authors.lastname: Pfeifer
authors.forename: Arkadiusz
authors.initials: A
authors.lastname: Piotrowski
authors.forename: Adam
authors.initials: A
authors.lastname: Bogdan
authors.forename: Wojciech
authors.initials: W
authors.lastname: Kloc
authors.forename: Johanna
authors.initials: J
authors.lastname: Sandgren
authors.forename: Tommie
authors.initials: T
authors.lastname: Olofsson
authors.forename: Göran
authors.initials: G
authors.lastname: Hesselager
authors.forename: Erik
authors.initials: E
authors.lastname: Blomquist
authors.forename: Jan
authors.initials: J
authors.lastname: Komorowski
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.forename: Carl E G
authors.initials: CE
authors.lastname: Bruder
authors.forename: Jan P
authors.initials: JP
authors.lastname: Dumanski
authors.forename: Teresita
authors.initials: T
authors.lastname: Díaz de Ståhl
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D002869:Chromosome Aberrations; D022202:Chromosomes, Artificial, Bacterial; D055028:Comparative Genomic Hybridization; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling; D052138:Genes, Neoplasm; D015894:Genome, Human; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D009857:Oncogenes; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D012333:RNA, Messenger