MGMT testing—the challenges for biomarker-based glioma treatment

Abstract

Many patients with malignant gliomas do not respond to alkylating agent chemotherapy. Alkylator resistance of glioma cells is mainly mediated by the DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT). Epigenetic silencing of the MGMT gene by promoter methylation in glioma cells compromises this DNA repair mechanism and increases chemosensitivity. MGMT promoter methylation is, therefore, a strong prognostic biomarker in paediatric and adult patients with glioblastoma treated with temozolomide. Notably, elderly patients (>65-70 years) with glioblastoma whose tumours lack MGMT promoter methylation derive minimal benefit from such chemotherapy. Thus, MGMT promoter methylation status has become a frequently requested laboratory test in neuro-oncology. This Review presents current data on the prognostic and predictive relevance of MGMT testing, discusses clinical trials that have used MGMT status to select participants, evaluates known issues concerning the molecular testing procedure, and addresses the necessity for molecular-context-dependent interpretation of MGMT test results. Whether MGMT promoter methylation testing should be offered to all individuals with glioblastoma, or only to elderly patients and those in clinical trials, is also discussed. Justifications for withholding alkylating agent chemotherapy in patients with MGMT-unmethylated glioblastomas outside clinical trials, and the potential role for MGMT testing in other gliomas, are also discussed. What is the role for MGMT testing in other gliomas? The answers to these issues depend not only on data from controlled clinical trials, but also on the availability of alternative treatment options to alkylating agents treatment, as well as on the access to molecular testing and its sensitivity and specificity.

Prognostic Relevance of Tumor Purity and Interaction with MGMT Methylation in Glioblastoma

“…Importantly, a prognostic value is suggested not only for a dichotomous MGMT promoter methylation status but also for the extent of methylation (1). It is therefore critical to standardize tumor purity of the input material for reproducible results (2). However, systematic investigation of tumor purity has been hindered by the lack of scalable assays.…”

Epigenetic Mechanisms Underlying the Pathogenesis of Neurogenetic Diseases

“…For example, prevailing methods for diagnosing imprinting disorders, such as Prader-Willi syndrome and Angelman syndrome, employ a combination of genetic and epigenetic analyses. The DNA methylation status of the MGMT gene promoter in glioma, which mediates responsiveness to the alkylating agent temozolomide, is increasingly being utilized for making treatment decisions in selected populations (i.e., elderly patients with glioblastoma and those with anaplastic glioma lacking IDH1/2 mutations) [125]. Also, the US Food and Drug Administration recently approved a sensitive noninvasive screening assay for colorectal cancer that examines a panel of markers, including KRAS mutations and NDRG4 and BMP3 methylation status [126].…”

Targeting DNA Repair Mechanisms to Treat Glioblastoma

“…In nearly a decade since the publications of these papers, the conclusion that MGMT promoter methylation sensitizes malignant glioma to temozolomide has been confirmed in multiple clinical and cohort studies [35][36][37][38]. MGMT promoter methylation status is an important prognostic biomarker and it appears that MGMT methylation status should be considered when formulating the treatment plan [39].…”