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. 2010 Mar;97(1):33-40.
doi: 10.1007/s11060-009-0004-4. Epub 2009 Aug 25.

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

Sean M McBride  1 , 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
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Activation of PI3K/mTOR pathway occurs in most adult low-grade gliomas and predicts patient survival

Sean M McBride et al. J Neurooncol. 2010 Mar.

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.

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Figures

Fig. 1
Fig. 1
Examples of scores of 3 for each of the four immunohistochemical assays performed; each of the four panels in the figure displays a separate tumor that received a score of 3 for PTEN, phospho-PRAS40, phospho-S6 (Ser235/236), or phospho-S6 (240/244), respectively
Fig. 2
Fig. 2
Kaplan-Meier plots by molecular marker status. The vertical tick marks represent patients censored for survival at the time of analysis. P-values are based on the exact log-rank test
See this image and copyright information in PMC

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