gms | German Medical Science

Objective: MGMT is a repair protein that in DNA removes alkylating substances from the O₆-guanine. This results in resistence against mutagenic and cytotoxic damage, caused by certain carcinogenes and chemotherapeutics. The high variability of the MGMT amount in different tumors leads to an unequal response of alkylating substances. Therefore, the control of this reaction is of particular clinical interest. In the present study we investigated promoter hypermethylation and expression of the MGMT gene in primary gliomas with different WHO grades and their respective recurrences.

Methods: Hypermethylation of the MGMT promoter region was examined in fresh frozen tumor tissue taken during surgery from 20 patients with primary gliomas and at least two corresponding recurrent tumors. Using methylation-specific PCR (MSP) of bisulfite-modified DNA, MGMT methylation has been investigated semiquantitatively in 65 tissue samples. In addition, in all samples the expression of the MGMT protein was examined by immunohistochemistry.

Results: In our fresh frozen tissue bank, out of 3021 patients we found 20 patients, where tissue of a primary glioma and at least two corresponding recurrences were available. The observation span was 1 to 12 years with a median of 5,5 years. There was a distinct increase in the methylation status in 11 out of 13 patients with a malignization of the recurrent glioma (WHO°II to WHO°III), whereas recurrent low grade gliomas confirmed previous results. The progression from a WHO°III to a WHO°IV tumor (4/4) again corresponded with an increase in the percentage of methylation, but to a much smaller extent than from WHO°II to WHO°III. In contrast, recurrences of all primary and secondary glioblastomas (8/8) showed a stable or reduced methylation of the MGMT promoter region.

Conclusions: The absolute amount of MGMT methylation showed a high rate of interindividual variation. Nevertheless in the individual patient, we found a direct correlation of an increase in the methylation status to tumor progression in most patients, especially during malignization of the tumors (WHO°II to WHO°III or WHO°IV, respectively). Interestingly, in glioblastoma a distinct regressive development could be observed during recurrence. This is in accordance with the clinical observation of an increased resistance against alkylating substances in glioblastoma recurrences.