Article
MGMT methylation status remains unchanged in recurrent malignant gliomas after radio-/chemotherapy
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Published: | May 20, 2009 |
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Objective: Epigenetic silencing of the MGMT DNA-repair gene has been linked to a favourable prognosis in de-novo malignant gliomas treated with alkylating agents. In patients with recurrent tumors after radio-/chemotherapy, it has been hypothesized that tumor progression might be correlated with a shift towards the unmethylated MGMT promoter status due to treatment-responsive glioma cell selection. The current prospective study was conducted to determine the MGMT promoter status in malignant gliomas before and after radio-/chemotherapy.
Methods: Patients with inoperable de-novo anaplastic astrocytomas (AA; n=11) and glioblastomas (GBM; n=13) were included. Histopathological diagnosis and molecular genetic profiling was performed in the de-novo and recurrent tumor situation using at least two tissue samples from different sites of the tumor, obtained from stereotactic biopsy procedures. MGMT methylation has been determined by methylation-specific PCR and sequencing methods, which can successfully be applied to small biopsy samples as published elsewhere (Int J Cancer, 2007). Standard treatment paradigms included primary RT/chemotherapy in case of AA and the EORTC-protocol in GBM. Re-biopsy was indicated in case of a MRI-based suspicion of tumor progression/recurrence. This study is part of a multi-center analysis performed by the German Glioma Network.
Results: Twenty-four patients were included (AA: N=11, GBM: N=13). Methylated (n= 13) and unmethylated (n=11) tumors were balanced with respect to age, gender, WHO grade, KPS, tumor size and location. Seven out of 11 de-novo AA and 8 out of 13 GBM were methylated at the MGMT promoter. Primary treatment included radiotherapy (n=8) and/or chemotherapy (n=3) in patients with AA. All GBM patients were treated according to the EORTC protocol. The median progression-free survival was 11 months. At the time of tumor progression, molecular genetic profiling exhibited unchanged MGMT methylation status compared to the de-novo situation in all tumors (24/24).
Conclusions: Radio-/chemotherapy did not change the MGMT status in malignant gliomas indicating that tumor progression can not be simply explained by a survival advantage of treatment resistant unmethylated glioma cells. Future studies have to evaluate the prognostic relevance of the MGMT promoter methylation status with respect to post-recurrence survival.