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. 2007 Jul;9(3):271-9.
doi: 10.1215/15228517-2007-003. Epub 2007 May 15.

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

John K Wiencke  1 , 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, David Stokoe
Affiliations

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

John K Wiencke et al. Neuro Oncol. 2007 Jul.

Abstract

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.

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Figures

Fig. 1
Fig. 1
(A) Methylation analysis of the PTEN promoter region by methylation-specific PCR. DNA from the indicated tumor samples and from normal tissues was treated with sodium bisulfite and subjected to PCR with methylation- and unmethylation-specific primers. All methylation-positive brain tumor tissues, oligoastrocytoma (OA) 5, astrocytoma (Astro) 10, and glioblastoma multiforme (GBM) 3, demonstrated both methylated and unmethylated products, indicating the likelihood of normal cell contamination. The negative brain tumor tissues and normal brain tissues demonstrated unmethylated products only. MW, molecular weight marker; M, methylated; U, unmethylated. (B) Methylation analysis of the PTEN promoter in secondary GBM. DNA from 11 secondary GBM tumors was isolated and treated with sodium bisulfite. PCR was performed using methylation- and unmethylation-specific primers, and the products were separated by electrophoresis. Abbreviations: MW, molecular weight marker; M, methylated; U, unmethylated.
Fig. 2
Fig. 2
Immunohistochemical staining for phospho-PKB/Akt in low-grade astrocytomas and oligoastrocytomas. Eight-micrometer sections from the indicated tumors were stained using a primary antibody recognizing the Ser-473 phosphorylated form of PKB/Akt. All images are at the same magnification (magnification ×200). The left column demonstrates negative staining in a grade II astrocytoma (Astro 5) and oligoastrocytoma (OA 13), as well as a section of normal cortex used as a negative control. The right column represents examples of tumors with positive PKB/Akt staining (Astro 3 and OA 11), as well as a glioblastoma multiforme sample with a PTEN mutation used as an external positive control.
Fig. 3
Fig. 3
Schematic diagram depicting regions of methylation demonstrated for PTEN and PTEN pseudogene (ϕPTEN). The black elongated rectangle represents the PTEN transcribed region, and the initiating methionine codon is indicated. The black line extending to the left of the rectangle represents the PTEN promoter. The hatched rectangle represents the PTEN pseudogene sequence on chromosome 9 showing the region of high homology to the PTEN transcript. Tumor-associated PTEN methylation has been reported in regions a,–, b, and c. Methylation of the PTEN pseudogene has been demonstrated in Zysman et al.
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References

    1. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344:1031–1037. - PubMed
    1. Cools J, DeAngelo DJ, Gotlib J, et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med. 2003;348:1201–1214. - PubMed
    1. van Oosterom AT, Judson I, Verweij J, et al. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet. 2001;358:1421–1423. - PubMed
    1. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib. Science. 2004;304:1497–1500. - PubMed
    1. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129–2139. - PubMed

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