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Clinical Cancer Research Vol. 8, 1100-1106, May 2002
© 2002 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Dysregulation of PTEN and Protein Kinase B Is Associated with Glioma Histology and Patient Survival1

Ralph P. Ermoian2, Constance S. Furniss2, Kathleen R. Lamborn, Daniel Basila, Mitchel S. Berger, Alexander R. Gottschalk, M. Kelly Nicholas, David Stokoe3 and Daphne A. Haas-Kogan

Departments of Radiation Oncology [R. P. E., C. S. F., D. B., A. R. G., D. A. H-K.], Brain Tumor Research Center and Neurosurgery [K. R. L., M. S. B., M. K. N., D. S., D. A. H-K.], Cancer Research Center [D. S.], The University of California, San Francisco, California 94143

Purpose: This study assessed whether putative effectors of phosphatidylinositol3-kinase, including PTEN, protein kinase B (PKB), and p27kip1, correlate with each other, with glioma histology, and with patient outcome.

Experimental Design: Components of the phosphatidylinositol 3-kinase signaling cascade were characterized in 25 glioblastoma multiforme (GBM) tumors, 8 grade II oligoastrocytomas, and 13 normal human brain specimens. The protein levels of PTEN and p27kip1 were assessed by immunoblot analyses. PKB kinase activity was evaluated through the expression level of the phosphorylated (activated) PKB protein and the ability of PKB to phosphorylate a specific peptide substrate in vitro. Cox regression analyses between expression/activity variables and survival were performed across and within histology types. Actual value for expression/activity was used as a continuous variable. Survival time was displayed by Kaplan Meier.

Results: A strong inverse correlation was evident between PTEN levels and both phosphorylated PKB expression (P < 0.01) and PKB activity (P = 0.01). p27kip1 levels did not correlate with PTEN expression or PKB activity. A significant association was evident between PTEN expression level and histology (P < 0.01). PTEN levels were highest in normal brain, lowest in GBM tumors, and intermediate in grade II oligoastrocytomas. PKB activity and phosphorylated PKB levels differed significantly among histologies, whereas p27kip1 levels exhibited no association with histology. PTEN expression correlated significantly with survival time within the entire cohort (P < 0.01) and was associated with survival within the subgroup of GBM tumors (P = 0.11).

Conclusions: Reduced PTEN expression is ubiquitous among GBM tumors and may play a role in the development of low-grade gliomas. PTEN inactivation in gliomas portends a particularly aggressive clinical behavior.




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Molecular Cancer Research Cancer Prevention Research
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Copyright © 2002 by the American Association for Cancer Research.