Activation of PI3K/mTOR pathway occurs in most adult low-grade gliomas and predicts patient survival

Sean M. McBride, Daniel A. Perez, Mei Yin Polley, Scott R. Vandenberg, Justin S. Smith, Shichun Zheng, Kathleen R. Lamborn, John K. Wiencke, Susan M. Chang, Michael D. Prados, Mitchel S. Berger, David Stokoe, Daphne A. Haas-Kogan

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

Recent evidence suggests the Akt-mTOR pathway may play a role in development of low-grade gliomas (LGG). We sought to evaluate whether activation of this pathway correlates with survival in LGG by examining expression patterns of proteins within this pathway. Forty-five LGG tumor specimens from newly diagnosed patients were analyzed for methylation of the putative 5′-promoter region of PTEN using methylation-specific PCR as well as phosphorylation of S6 and PRAS40 and expression of PTEN protein using immunohistochemistry. Relationships between molecular markers and overall survival (OS) were assessed using Kaplan-Meier methods and exact log-rank test. Correlation between molecular markers was determined using the Mann-Whitney U and Spearman Rank Correlation tests. Eight of the 26 patients with methylated PTEN died, as compared to 1 of 19 without methylation. There was a trend towards statistical significance, with PTEN methylated patients having decreased survival (P = 0.128). Eight of 29 patients that expressed phospho-S6 died, whereas all 9 patients lacking p-S6 expression were alive at last follow-up. There was an inverse relationship between expression of phospho-S6 and survival (P = 0.029). There was a trend towards decreased survival in patients expressing phospho-PRAS40 (P = 0.077). Analyses of relationships between molecular markers demonstrated a statistically significant positive correlation between expression of p-S6(235) and p-PRAS40 (P = 0.04); expression of p-S6(240) correlated positively with PTEN methylation (P = 0.04) and negatively with PTEN expression (P = 0.03). Survival of LGG patients correlates with phosphorylation of S6 protein. This relationship supports the use of selective mTOR inhibitors in the treatment of low grade glioma.

Original languageEnglish (US)
Pages (from-to)33-40
Number of pages8
JournalJournal of neuro-oncology
Volume97
Issue number1
DOIs
StatePublished - Mar 2010

Keywords

  • Low grade glioma
  • MTOR
  • PRAS40
  • PTEN
  • Rapamycin

ASJC Scopus subject areas

  • Oncology
  • Neurology
  • Clinical Neurology
  • Cancer Research

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