Methylation of the PTEN promoter defines low-grade gliomas and secondary glioblastoma.
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.
Wiencke
John K
JK
Department of Neurological Surgery and Brain Tumor Research Center, University of California, San Francisco, San Francisco, CA 94143, USA. John.Wiencke@ucsf.edu
Zheng
Shichun
S
Jelluma
Nanette
N
Tihan
Tarik
T
Vandenberg
Scott
S
Tamgüney
Tanja
T
Baumber
Rachel
R
Parsons
Ramon
R
Lamborn
Kathleen R
KR
Berger
Mitchel S
MS
Wrensch
Margaret R
MR
Haas-Kogan
Daphne Adele
DA
Stokoe
David
D
D000328:Adult; D014408:Biomarkers, Tumor; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics*; D019175:DNA Methylation; D005819:Genetic Markers; D005909:Glioblastoma / Q000235:genetics* / Q000556:secondary; D005910:Glioma / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic
D014408:Biomarkers, Tumor; D005819:Genetic Markers; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human