Survival of Patients with Glioblastoma Multiforme is not Influenced by Altered Expression of P16, P53, EGFR, MDM2 or Bcl‐2 Genes

Abstract

Deregulated expression of one or more growth control genes including p16, p53, EGF receptor (EGFR), MDM2 or Bcl-2 may contribute to the treatment resistance phenotype of GBM and generally poor patient survival. Clinically, GBM have been divided into two major groups defined by (1) histologic progression from a low grade tumor ("progressive" or "secondary" GBM) contrasted with (2) those which show initial clinical presentation without a prior history ("de novo" or "primary" GBM). Using molecular genetic analysis for p53 gene mutations together with immunophenotyping for overexpression of EGFR, up to four GBM variants can be distinguished, including the p53+/EGFR- progressive or the p53-/EGFR+ de novo variant. We examined the survival of 80 adult patients diagnosed with astrocytic GBM stratified by age category (>40, 41-60 or 61-80) to determine whether alterations in any one given growth control gene or whether different genetic variants of GBM (progressive versus de novo) were associated with different survival outcomes. Survival testing using Kaplan-Meier plots for GBM patients with or without altered expression of p16, p53, EGFR, MDM2 or Bcl-2 showed no significant differences by age group or by gene expression indicating a lack of prognostic value for GBM. Also the clinical outcome among patients with GBM showed no significant differences within each age category for any GBM variant including the progressive and de novo GBM variants indicating similar biologic behavior despite different genotypes. Using a pairwise comparison, one-third of the GBM with normal p16 expression showed accumulation of MDM2 protein and this association approached statistical significance (0.01 < P < 0.05) using the Bonferroni procedure. These GBM may represent a variant in which the p19ARF/MDM2/p53 pathway may be deregulated rather than the p16/cyclin D-CDK4/Rb pathway.

Immunohistochemical expression of p53 and p21 in gliomas: a clinicopathological study

“…Loss or mutation of p53 is especially common in gliomas and is reported to be the earliest detectable event in their development 8 . In the present study, p53 was detected in 53.3% of gliomas, a finding that is comparable with that reported by other authors from Brazil and USA who found positive expression in about 54% of their cases 5,9 . In our series, p53 expression was observed to be more frequent among patients older than 30 years age, a finding which was also observed in other studies, 10,11 which probably related to the higher glioma grade occurring with increasing age 12 .…”

PBEF1/NAmPRTase/Visfatin: A potential malignant astrocytoma/glioblastoma serum marker with prognostic value

“…In GBM patients, while the prognostic significance of clinical variables in predicting survival have been clearly defined, altered protein expression of the well known genetic alteration found in these tumors, like overexpression of p53 and EGFR expression, have individually failed to give a clear cut prognostic significance, with confounding results in different studies. [13][14][15] Therefore, for the purpose of multivariate analysis, we immunostained the sections to study the expression of p53 and EGFR in order to analyse the significance of their co-expression with PBEF1 with respect to patient survival. Correlating the expression of PBEF1 with survival among GBM patients, in univariate analysis, the median survival of the group which was positive for PBEF1 (black line) was lesser than that of the group negative for PBEF1 (grey dotted line), albeit with lack of statistical significance (12 months vs. 16 months respectively, p = 0.16; Fig.…”

Flavopiridol Induces Mitochondrial-Mediated Apoptosis in Murine Glioma GL261 Cells via Release of Cytochrome c and Apoptosis Inducing Factor

“…1 Most GBM, similar to many other human cancers, have genetic alterations in one of the components of the Rb pathway (Rb/CDK-4-cyclin-D1/p16 INK4a ). [2][3][4] Changes in the phosphorylation state of Rb controls progression of a cell from G 1 into S-phase. Rb is phosphorylated by one of several cyclin-dependent kinases (CDKs) such as CDK4 in complex with cyclin D1, which serves to inactivate Rb there by promoting cell cycling.…”