Screening of genomic imbalances in glioblastoma multiforme using high-resolution comparative genomic hybridization

Abstract

Comparative genomic hybridization (CGH) is a molecular cytogenetic technique that allows the genomewide analysis of DNA sequence copy number differences. We applied conventional CGH and the recently developed high-resolution CGH (HR-CGH) to tumour samples from 18 patients with glioblastoma multiforme (GBM) in order to compare the sensitivity of CGH and HR-CGH in the screening of chromosomal abnormalities. The abnormalities were studied in topologically different central and peripheral tumour parts. A total of 78 different changes were observed using CGH (0-16 per tumour, median 3.5) and 154 using HR-CGH (0-21 per tumour, median 6). Using HR-CGH, losses were more frequent than gains. The representation of the most prominent changes revealed by both methods was similar and was comprised of the amplification of 7q12 and 12q13-q15, the gain of 7, 3q and 19, and the loss of 10, 9p, and 13q. However, HR-CGH detected certain other abnormalities (the loss of 6, 14q, 15q and 18q, and the gain of 19), which were rarely revealed by CGH. Using HR-CGH, the numbers and types of chromosomal changes detected in the central and peripheral parts of GBM were almost the same. The loss of chromosomes 10 and 9p and the gain of chromosomes 7 and 19 were the most frequent chromosomal alterations in both tumour parts. Our results from the GBM analysis show that HR-CGH technology can reveal new, recurrent genetic alterations involving the genes known to participate in tumorigenesis and in the progression of several human malignancies, thus allowing for a more accurate genetic characterization of these tumours.

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

“…Through this approach, we confirmed the existence of previously reported genomic abnormalities for these three chromosomes. [13][14][15] In addition, use of high-resolution SNP arrays allowed accurate and detailed delineation of those sequences affected by CN changes (eg, gains, amplifications, and homozygous or heterozygous Figure 3. Overall survival curves of glioblastoma patients (n ϭ 35) from our patients (A-C) and our patients plus cases from five other series (154 total cases) from the literature (D-F), according to the different cytogenetic patterns of alteration detected for chromosomes 7, 9, and 10 (A and D) and the presence of EGFR amplification in the whole series (B and E) and among patients older than 60 years (C and F).…”

“…[1][2][3][4][5][6][7][8][9][10][11] Although no common genetic signature has been detected in all gliomas, multiple chromosomal changes have been described so far, which frequently include gains of chromosome 7 and deletions of chromosomes 9 and 10 and to a less extent also of chromosomes 1 and 19. [12][13][14] These genetic changes are associated with amplification of oncogenes [eg, epidermal growth factor receptor (EGFR)] together with deletion and/or mutation of tumor suppressor genes [eg, tumor protein p53 (TP53), phosphatase and tensin homolog (PTEN), and cyclin-dependent kinase inhibitor 2A (p16/CDKN2A)]. 15 Altogether, these results point out the potential involvement of different signaling pathways in gliomas, with alterations of chromosome 7, 9, and 10 participating in the most frequent tumor subtypes (eg, glioblastoma).…”

Glioblastoma Multiforme Oncogenomics and Signaling Pathways

“…Particularly common regions of loss include areas on 1p, 6q, 9p, 10p, 10q, 13q, 14q, 15q, 17p, 18q, 19q, 22q, and Y 5–10. Loss of heterozygosity (LOH) on chromosome 10 is the most frequent genetic alteration in GBM, occurring in 60%–80% of cases 11.…”

“…Gains of gene expression due to genetic alterations at the genomic level have also been demonstrated in GBM in the form of duplication of entire chromosomes, intra-chromosomal amplification of specific alleles, extra-chromosomal amplification (often in the form of double minutes [dmins]), and activating mutations 10,19,20. These forms of increased gene expression (oncogenic) occur much less frequently than losses of gene expression as noted above.…”

Characterization and gene expression profiling in glioma cell lines with deletion of chromosome 19 before and after microcell‐mediated restoration of normal human chromosome 19

“…The astrocytoma group (mostly GBMs) expressed BCL2L12 at a significantly higher level than the group of mixed oligoastrocytomas or oligodendrogliomas. It is important to note that gain of chromosome 19 was not observed in the group of astrocytomas, an alteration that is sometimes seen in GBM (Vranova et al, 2007). Previous work has demonstrated an increased expression of BCL2L12 in GBM compared with the surrounding normal brain by RT-PCR (Stegh et al, 2007).…”