Journal of Neuro-Oncology 48: 89–94, 2000. © 2000 Kluwer Academic Publishers. Printed in the Netherlands. Laboratory Investigation Molecular analysis of the PTEN , TP53 and CDKN2A tumor suppressor genes in long-term survivors of glioblastoma multiforme J¨ urgen A. Kraus 1 , Nicole Glesmann 1 , Martina Beck 1 , Dietmar Krex 2 , Thomas Klockgether 1 , Gabriele Schackert 2 and Uwe Schlegel 1 1 Department of Neurology, University of Bonn Medical Center, Bonn; 2 Department of Neurosurgery, University of Dresden, Dresden, Germany Key words: glioblastoma multiforme, long-term survival, TP53, PTEN, CDKN2A, tumor suppressor gene Summary Despite multimodal therapy, glioblastoma multiforme (GBM) is associated with a poor prognosis with a median survival of less than 1 year. However, a small number of patients with GBM shows survival times of several years. Although clinical features like age and performance status at diagnosis are well known prognostic parameters, molecular markers for prognosis of overall survival are still lacking. Therefore, we compared 2 age- and gender- matched groups of GBM patients with different post-operative time to tumor progression (TTP), defined as ‘short- term’ for TTP of less than 6 months (n = 21), and ‘long-term’ for TTP of more than 24 months (n = 21) for genetic alterations of the PTEN , CDKN2A and TP53 genes as well as overexpression of the EGFR, p53 and Mdm2 proteins. For the GBMs with ‘short-term’ TTP vs. ‘long-term’ TTP, the studies revealed PTEN mutations in 4/21 vs. 2/21, TP53 mutations in 5/21 vs. 8/21, homozygous deletion of the CDKN2A gene in 5/21 vs. 6/21, overexpression of EGFR in 7/20 vs. 10/20, accumulation of p53 protein in 9/20 vs. 7/20 and of Mdm2 protein in 0/20 vs. 1/20 cases studied. Taken together, our data indicate that mutations of the PTEN and TP53 tumor suppressor genes, homozygous deletion of the CDKN2A gene as well as overexpression of the EGFR, p53 and Mdm2 proteins lack prognostic significance for overall survival time in patients with GBMs. Abbreviations: GBM – glioblastoma multiforme; EGFR – epidermal growth factor receptor; SSCP – single strand conformation polymorphism; WHO – World Health Organization; LOH – loss of heterozygosity; TTP – time to tumor progression. Introduction Glioblastoma multiforme (WHO grade IV, GBM) is the most common primary brain tumor accounting for about 50% of all gliomas and for 12–15% of all intracranial tumors [1]. Despite multimodal treat- ment regimens, the prognosis for the vast majority of GBM patients remains poor. Median survival is less than 1 year [2] and has changed little over the past 2 decades [3]. However, a small subgroup of GBM patients has a better clinical outcome, with a small num- ber of patients surviving several years [4–7]. Although certain clinical features, including most notably age and performance status at diagnosis, are well known prognostic parameters [2,7–9], it is obvious that other, yet unknown genetic and/or epigenetic factors con- tribute to the unusually long survival of individual glioblastoma patients. The molecular genetic alterations associated with the development and progression of human gliomas have been intensively studied over the past years [10,11]. The TP53 gene is a frequent target for mutations in GBMs and its gene product (p53) is involved in the regulation of the cell cycle, apoptosis, and DNA repair [12]. The activity of p53 is regulated by the Mdm2 protein, which inhibits p53-mediated transcrip- tional activation of several genes, including MDM2 itself, resulting in proteolytic degradation of p53 by the ubiquitin-proteasome pathway [13]. Amplification and overexpression of the MDM2 gene has been detected in