Methylation of the PTEN promoter defines low-grade gliomas and secondary glioblastoma
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).
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Abstract |
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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.
Keywords: low-grade glioma, methylation, PKB/Akt, PTEN, secondary glioblastoma
Received June 16, 2006; Accepted October 2, 2006
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