title: Activation of PI3K/mTOR pathway occurs in most adult low-grade gliomas and predicts patient survival.
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.
authors.affiliation: Radiation Oncology Program, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sean M
authors.initials: SM
authors.lastname: McBride
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Perez
authors.forename: Mei-Yin
authors.initials: MY
authors.lastname: Polley
authors.forename: Scott R
authors.initials: SR
authors.lastname: Vandenberg
authors.forename: Justin S
authors.initials: JS
authors.lastname: Smith
authors.forename: Shichun
authors.initials: S
authors.lastname: Zheng
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Lamborn
authors.forename: John K
authors.initials: JK
authors.lastname: Wiencke
authors.forename: Susan M
authors.initials: SM
authors.lastname: Chang
authors.forename: Michael D
authors.initials: MD
authors.lastname: Prados
authors.forename: Mitchel S
authors.initials: MS
authors.lastname: Berger
authors.forename: David
authors.initials: D
authors.lastname: Stokoe
authors.forename: Daphne A
authors.initials: DA
authors.lastname: Haas-Kogan
mesh_terms: D000328:Adult; D001932:Brain Neoplasms / Q000188:drug therapy / Q000401:mortality*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy / Q000401:mortality*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011237:Predictive Value of Tests; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012189:Retrospective Studies; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D018709:Statistics, Nonparametric; D013447:Sulfites / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases; D055815:Young Adult
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D012694:Serine; D013447:Sulfites; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C494929:PTEN protein, human; C042345:hydrogen sulfite
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