Characterization of novel and complex genomic aberrations in glioblastoma using a 32K BAC array

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 -