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.

Detailed Characterization of Alterations of Chromosomes 7, 9, and 10 in Glioblastomas as Assessed by Single-Nucleotide Polymorphism Arrays

“…These findings strengthen the hypothesis that suggests the presence of additional candidate tumor suppressor genes mapped to this region. 67 Overall, approximately three-quarters of all glioblastomas analyzed showed chromosome 10 losses, which most frequently consisted of monosomy 10 and cnLOH of an entire chromosome 10. These findings point to the loss of more than one tumor suppressor gene, localized both in the short and the long arms of this chromosome.…”

Frequent genetic differences between matched primary and metastatic breast cancer provide an approach to identification of biomarkers for disease progression

“…On the basis of large genomic clones with an average resolution of 50-100 kb per data point, [16][17][18]32 we applied a well established, thoroughly validated array covering B99% of the human genome. The average resolution of our analysis is more than an order of magnitude higher than that used in the recent array-CGH analysis comparing ALN metastases and primary tumors.…”

Epidermal Growth Factor Receptor (EGFR)-mediated Positive Feedback of Protein-tyrosine Phosphatase ϵ (PTPϵ) on ERK1/2 and AKT Protein Pathways Is Required for Survival of Human Breast Cancer Cells

“…Global genomic analysis identified PTPRE as a gene deleted in glioblastoma and whose expression is down-regulated in malignant pheochromocytoma (36,37). In breast cancer, DNA microarray analysis revealed up-regulation of PTP⑀ in invasive breast carcinomas versus normal breast tissue (38).…”