MGMT promoter methylation in malignant gliomas: ready for personalized medicine?

Abstract

The DNA repair enzyme O 6 -methylguanine-DNA methyltransferase (MGMT) antagonizes the genotoxic effects of alkylating agents. MGMT promoter methylation is the key mechanism of MGMT gene silencing and predicts a favorable outcome in patients with glioblastoma who are exposed to alkylating agent chemotherapy. This biomarker is on the verge of entering clinical decision-making and is currently used to stratify or even select glioblastoma patients for clinical trials. In other subtypes of glioma, such as anaplastic gliomas, the relevance of MGMT promoter methylation might extend beyond the prediction of chemosensitivity, and could reflect a distinct molecular profile.Here, we review the most commonly used assays for evaluation of MGMT status, outline the prerequisites for standardized tests, and evaluate reasons for difficulties in reproducibility. We critically discuss the prognostic and predictive value of MGMT silencing, reviewing trials in which patients with different types of glioma were treated with various chemotherapy schedules, either upfront or at recurrence. Standardization of MGMT testing requires comparison of different technologies across laboratories, and prospectively validated cut-off values for prognostic or predictive effects. Moreover, future clinical trials will need to determine, for each subtype of glioma, the degree to which MGMT promoter methylation is predictive or prognostic, and whether testing should become routine clinical practice.

Downregulation of PRDX1 by promoter hypermethylation is frequent in 1p/19q-deleted oligodendroglial tumours and increases radio- and chemosensitivity of Hs683 glioma cells in vitro

“…Mo¨llemann et al (2005) reported that 1p/19q-deleted oligodendroglial tumours frequently demonstrate promoter hypermethylation and reduced expression of the O(6)-methylguanine DNA methyltransferase (MGMT) gene, an aberration that has been linked to response to TMZ therapy in glioblastoma patients (Hegi et al, 2005) as well as response to chemo-and radiotherapy in anaplastic glioma patients (Wick et al, 2009). However, although MGMT inactivation undoubtedly is of relevance for TMZ sensitivity (for review see Weller et al, 2010), a mechanistic role of MGMT in mediating radiosensitivity has not been demonstrated, thus suggesting the involvement of genetic/epigenetic alterations in other genes. Our in vitro results clearly demonstrate that not only TMZ-induced apoptosis is strongly (more than fivefold) increased after PRDX1 silencing in Hs683 cells, but they also show significantly higher sensitivity of PRDX1-knockdown Hs683 cells to ionizing irradiation.…”

Promoter methylation and expression of MGMT and the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 in paired primary and recurrent glioblastomas

“…Other methods for MGMT expression analysis, e.g., by Western blot analysis 28 or a quantitative PCR, were not addressed here but may be similarly confounded by the presence of non-neoplastic cells in the tumor tissue. 4,7 Role of aberrant MMR genes in recurrent glioblastomas Several studies have suggested a role of MMR gene alterations in the resistance to TMZ and glioblastoma relapse. Friedman et al 8 demonstrated involvement of MSH2 deficiency in the methylator resistance of a human glioblastoma xenograft.…”

“…Aberrant MGMT promoter methylation may lead to transcriptional repression and lower MGMT protein expression in tumor cells, which may explain the clinical association of MGMT promoter methylation with longer survival of TMZ-treated glioblastoma patients. 4 Nevertheless, virtually all glioblastomas relapse after the initial therapy, including the best prognostic subgroup of completely resected and MGMT promoter-methylated tumors. 7 The molecular mechanisms underlying therapy resistance and recurrence of glioblastomas are still unclear.…”

Effect of temozolomide on male gametes: an epigenetic risk to the offspring?

“…Tumor cells expressing MGMT are resistant to alkylating agents, while those that lack the DNA-repair protein are more susceptible. In most cases, the silencing of MGMT is associated with methylation of the promoter [13]. Here, we observed that the MGMT promoter is methylated in sperm and that temozolomide treatment does not alter this pattern.…”