Cytogenetics and Molecular Genetics of Malignant Gliomas and Medulloblastoma

Abstract

Malignant gliomas and medulloblastomas which are the most common primary malignant brain tumours of adult and children, respectively, resemble other neurogenic tumours as they frequently contain gene amplification and show non-random loss of specific chromosomal regions. In gliomas the gene which is most often amplified, is the epidermal growth factor receptor gene. In many cases the gene is rearranged as well, producing abnormally small epidermal growth factor receptor proteins. More than 80% of tumours have lost chromosome 10 and losses of 9p13, 17p and 22 occur in subgroups of cases. 17p loss is associated with point mutations of the p53 gene, but the relevant genes in the other chromosomal regions remain to be identified. For medulloblastoma the most frequent chromosomal abnormality is i(17q). Whether or not p53 gene mutations are the targets of 17p losses in these tumours remains to be determined. Approximately 5% of medulloblastoma biopsies contain gene amplification, although the incidence in medulloblastoma cell lines is more than 80%. c-myc is the gene which is most frequently amplified in this tumour type. The relationship of these various molecular genetic abnormalities to the biology of the tumours and the course of the patients remains largely unexplored.

p53 protein in low-grade astrocytomas: a study with long-term follow-up

“…This is in keeping with the demonstration that loss of heterozygosity for loci on the short arm of chromosome 17 (17p) (where the p53 gene is located) is shared by cells in each malignancy stage (ElAzouzi et al, 1989;James et al, 1989James et al, , 1990Bigner & Vogelstein, 1990;Venter & Thomas, 1991;Cavenee, 1992;von Diemling et al, 1993). p53 gene and protein alterations could indeed be an early event in tumour progression, which may be associated with clinical aggressiveness.…”

“…The fact that the recurrent tumours that we could analyse were histologically malignant (one grade III astrocytoma and four glioblastomas) could be related to the fact that, once a tumour is composed mainly of a p53-positive genetically unstable cell population (Lane, 1992), the likelihood of further genetic damage is greater and specific additional structural changes, for example on chromosome 10, could be more frequent, leading to the development of a highly aggressive tumour (Bigner & Vogelstein, 1990;von Diemling et al, 1993). In this view the four recurrences with histological features of glioblastomas could be interpreted as type 1 glioblastomas according to von Diemling et al (1993).…”

New pattern of EGFR amplification in glioblastoma and the relationship of gene copy number with gene expression profile

“…9,10 Molecular studies demonstrated the amplification of several genes in these tumors, especially of the EGFR gene; the amplified sequences were found located on dmin, analyzed in a small number of cases by in situ hybridization of tumor metaphases. 15,16 However, studies by FISH in interphase nuclei are more frequent, displaying a considerable heterogeneity of EGFR copy number.…”

“…8 The first evidence of gene amplification in glioblastoma was provided by cytogenetic analyses that exhibited the presence of dmin. 9,10 Molecular screening for gene amplification revealed frequent amplification of the EGFR, observed in about 35-70% of glioblastomas. 8,11,12 Differences in the frequency of EGFR amplification are most probably due to different methods used, such as Southern blot, polymerase chain reaction (PCR), and fluorescent in situ hybridization (FISH).…”

PTEN signaling in brain: neuropathology and tumorigenesis

“…Interestingly, although PTEN mutations are observed frequently in GBM, they are rare in lowergrade astrocytic tumors (Louis et al, 2007). Although the sequence of mutational events in primary GBM is unknown, in secondary GBM, TP53 mutation is usually an early event occurring frequently in lower-grade astrocytic tumors (Bigner and Vogelstein, 1990); however, PTEN inactivation is not detected frequently until the transition to GBM. This suggests that PTEN loss does not confer a selective growth advantage early in astrocytic tumor development (Figure 3).…”