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Frequent promoter hypermethylation and low expression of the MGMT gene in oligodendroglial tumors
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| Zeitschriftentitel: | International Journal of Cancer |
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| Personen und Körperschaften: | , , , , |
| In: | International Journal of Cancer, 113, 2005, 3, S. 379-385 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Wiley
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| Schlagwörter: |
| Zusammenfassung: | <jats:title>Abstract</jats:title><jats:p>Allelic losses on the chromosome arms 1p and 19q have been associated with favorable response to chemotherapy and good prognosis in anaplastic oligodendroglioma patients, but the molecular mechanisms responsible for this relationship are as yet unknown. The DNA repair enzyme O<jats:sup>6</jats:sup>‐methylguanine DNA methyltransferase (MGMT) may cause resistance to DNA‐alkylating drugs commonly used in the treatment of anaplastic oligodendrogliomas and other malignant gliomas. We report on the analysis of 52 oligodendroglial tumors for <jats:italic>MGMT</jats:italic> promoter methylation, as well as mRNA and protein expression. Using sequencing of sodium bisulfite‐modified DNA, we determined the methylation status of 25 CpG sites within the <jats:italic>MGMT</jats:italic> promoter. In 46 of 52 tumors (88%), we detected <jats:italic>MGMT</jats:italic> promoter hypermethylation as defined by methylation of more than 50% of the sequenced CpG sites. Real‐time reverse transcription‐PCR showed reduced <jats:italic>MGMT</jats:italic> mRNA levels relative to non‐neoplastic brain tissue in the majority of tumors with hypermethylation. Similarly, immunohistochemical analysis showed either no or only small fractions of MGMT positive tumor cells. <jats:italic>MGMT</jats:italic> promoter hypermethylation was significantly more frequent and the percentage of methylated CpG sites in the investigated <jats:italic>MGMT</jats:italic> promoter fragment was significantly higher in tumors with loss of heterozygosity on chromosome arms 1p and 19q as compared to tumors without allelic losses on these chromosomes arms. Taken together, our data suggest that <jats:italic>MGMT</jats:italic> hypermethylation and low or absent expression are frequent in oligodendroglial tumors and likely contribute to the chemosensitivity of these tumors.</jats:p> |
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| Umfang: | 379-385 |
| ISSN: |
0020-7136
1097-0215 |
| DOI: | 10.1002/ijc.20575 |