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First published on May 15, 2007
This version was published on July 1, 2007
Neuro Oncol 2007 9(3):271-279; DOI:10.1215/15228517-2007-003
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Duke University Press

Basic and Translational Investigations

Methylation of the PTEN promoter defines low-grade gliomas and secondary glioblastoma

John K. Wiencke, Shichun Zheng, Nanette Jelluma, Tarik Tihan, Scott Vandenberg, Tanja Tamgüney, Rachel Baumber, Ramon Parsons, Kathleen R. Lamborn, Mitchel S. Berger, Margaret R. Wrensch, Daphne Adele Haas-Kogan and David Stokoe

Department of Neurological Surgery and Brain Tumor Research Center (J.K.W., S.Z., K.R.L., M.S.B., M.R.W., D.A.H.-K.), Department of Radiation Oncology (N.J., D.A.H.-K.), Department of Pathology (T. Tihan, S.V.), and Cancer Research Institute (T. Tamgüney, R.B., D.S.), University of California, San Francisco, San Francisco, CA 94143; and Institute of Cancer Genetics (R.P.), Columbia University, New York, NY; USA

Address correspondence to John K. Wiencke, Laboratory for Neuro and Molecular Epidemiology, 1st and Arguello, Ambulatory Care Bldg. AC-34, San Francisco, CA 94143-0441, USA (John.Wiencke{at}ucsf.edu).

Glioblastoma multiforme (GBM) can present as either de novo or secondary tumors arising from previously diagnosed low-grade gliomas. Although these tumor types are phenotypically indistinguishable, de novo and secondary GBMs are associated with distinct genetic characteristics. PTEN mutations, which result in activation of the phosphoinositide 3-kinase (PI3K) signal transduction pathway, are frequent in de novo but not in secondary GBMs or their antecedent low-grade tumors. Results we present here show that grade II astrocytomas, oligodendrogliomas, and oligoastrocytomas commonly display methylation of the PTEN promoter, a finding that is absent in nontumor brain specimens and rare in de novo GBMs. Methylation of the PTEN promoter correlates with protein kinase B (PKB/Akt) phosphorylation, reflecting functional activation of the PI3K pathway. Our results also demonstrate frequent methylation of the PTEN promoter in grade III astrocytomas and secondary GBMs, consistent with the hypothesis that these tumors arise from lower grade precursors. PTEN methylation is rare in de novo GBMs and is mutually exclusive with PTEN mutations. We conclude that methylation of the PTEN promoter may represent an alternate mechanism by which PI3K signaling is increased in grade II and III gliomas as well as secondary GBMs, a finding that offers new therapeutic approaches in these patients.

Key Words: low-grade glioma • methylation • PKB/Akt • PTEN • secondary glioblastoma




This article has been cited by other articles:


Home page
 J. Cell Sci.Home page
T. Tamguney and D. Stokoe
New insights into PTEN
J. Cell Sci., December 1, 2007; 120(23): 4071 - 4079.
[Abstract] [Full Text] [PDF]


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