TY - JOUR
T1 - Characterization of novel and complex genomic aberrations in glioblastoma using a 32K BAC array
AU - Nord, Helena
AU - Hartmann, Christian
AU - Andersson, Robin
AU - Menzel, Uwe
AU - Pfeifer, Susan
AU - Piotrowski, Arkadiusz
AU - Bogdan, Adam
AU - Kloc, Wojciech
AU - Sandgren, Johanna
AU - Olofsson, Tommie
AU - Hesselager, Göran
AU - Blomquist, Erik
AU - Komorowski, Jan
AU - von Deimling, Andreas
AU - Bruder, Carl E G
AU - Dumanski, Jan P
AU - Díaz de Ståhl, Teresita
PY - 2009/12
Y1 - 2009/12
N2 - 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.
AB - 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.
KW - Brain Neoplasms
KW - Chromosome Aberrations
KW - Chromosomes, Artificial, Bacterial
KW - Comparative Genomic Hybridization
KW - Female
KW - Gene Dosage
KW - Gene Expression Profiling
KW - Genes, Neoplasm
KW - Genome, Human
KW - Glioblastoma
KW - Humans
KW - In Situ Hybridization, Fluorescence
KW - Male
KW - Middle Aged
KW - Oligonucleotide Array Sequence Analysis
KW - Oncogenes
KW - Prognosis
KW - RNA, Messenger
KW - Reverse Transcriptase Polymerase Chain Reaction
U2 - 10.1215/15228517-2009-013
DO - 10.1215/15228517-2009-013
M3 - Journal article
C2 - 19304958
SN - 1522-8517
VL - 11
SP - 803
EP - 818
JO - Neuro-Oncology
JF - Neuro-Oncology
IS - 6
ER -
