Prognostic impact of molecular markers in a series of 220 primary glioblastomas

Abstract

BACKGROUND.In contrast to oligodendrogliomas, molecular predictors of prognosis have not been consistently found in glioblastomas. However, genetic studies show that glioblastomas consist of several genetic subtypes and raise the possibility that molecular alterations could be predictive of survival. METHODS.A search for loss of heterozygosity (LOH) on chromosome 1p, 9p, 10q, 19q, EGFR (epidermal growth factor receptor), CDK4, and MDM2 (mouse double minute) amplifications, CDKN2A (INK4A/ARF) homozygous deletions, p53 expression, was performed in a series of 220 primary glioblastomas. The molecular alterations were then correlated with each other to identify distinct molecular pathways and with clinical parameters and the course of the disease to identify prognostic markers. RESULTS.Nonrandom associations were found between EGFR amplification and LOH10q, LOH9p, and INK4A/ARF deletion, LOH1p and LOH19q, and MDM2 and CDK4 amplification, whereas mutual exclusions were found between p53 expression and EGFR amplification, LOH 9p/INK4A/ARF homozygous deletion, and MDM2 and CDK4 amplification. Age (P ϭ 4.10 -5 ) and performance status (P ϭ .003) were the main predictors of outcome. In contrast, molecular markers were of limited impact: MDM2 amplification correlated with poor outcome on both univariate and multivariate analysis (P ϭ .01) and EGFR amplification with good prognosis on multivariate analysis (P ϭ .02). CONCLUSION.Despite their limited prognostic impact, the genetic markers investigated here outline distinct molecular pathways involved in glioblastoma tumorigenesis and warrant broader molecular screening.

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and paclitaxel have cooperative in vivo effects against glioblastoma multiforme cells

“…Furthermore, although the p53 gene in SF767 is not deleted or mutated, other regulators of the p53 pathway may not in fact be intact and abrogate a wild-type response. Lending support to the broad antitumor effect of our treatment in both p53 genetic backgrounds in SF767 GBM tumors, there is not a great deal of correlation between therapeutic outcomes and p53 status in brain tumors (32), suggesting that in transformed cells, p53 gene status has diminished importance compared with normal untransformed cells. This is reassuring from the standpoint of an increased therapeutic index.…”

Interleukin-6 gene amplification and shortened survival in glioblastoma patients

“…This initial amplification event may induce instability along the length of this chromosomal arm, resulting in co-amplification of other genes. Of note, EGFR gene amplification has no clear prognostic value in GBM (Houillier et al, 2006). It may be possible that some of co-amplified (or independently amplified) genes are involved in glioma development and progression and are important for patient prognosis.…”

The protein kinase C-η isoform induces proliferation in glioblastoma cell lines through an ERK/Elk-1 pathway

“…In particular, 50% of primary GBMs are associated with epidermal growth factor receptor (EGFR) abnormalities (Nozaki et al, 1999;Mischel and Cloughesy, 2003;Houillier et al, 2006). EGFR dysregulation in GBMs arises from EGFR gene (egfr) amplification, mutation and overexpression.…”