Activation of PI3K/mTOR Pathway Occurs in Most Adult Low-Grade Gliomas and Predicts Patient Survival
Perez, Daniel A.
Vandenberg, Scott R.
Lamborn, Kathleen R.
Wiencke, John K.
Chang, Susan M.
Prados, Michael D.
Berger, Mitchel S.
Haas-Kogan, Daphne A.
Smith, Justin S.Note: Order does not necessarily reflect citation order of authors.
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CitationMcBride, Sean M., Daniel A. Perez, Mei-Yin Polley, Scott R. Vandenberg, Justin S. Smith, Shichun Zheng, Kathleen R. Lamborn, et al. 2009. Activation of PI3K/mTOR pathway occurs in most adult low-grade gliomas and predicts patient survival. Journal of Neuro-Oncology 97(1): 33-40.
AbstractRecent 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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