Common Molecular Marker for Glioma: MGMT

O⁶– O6-methylguanine-DNA methyltransferase (MGMT), located on chromosome 10q26, is a DNA repair enzyme that can rapidly repair DNA alkylation damage caused by alkylating agents, thereby maintaining genomic stability in cells. The promoter of the gene encoding the MGMT protein includes a CpG island rich in 97 CG dinucleotides (CpG sites). In normal tissues, CpG sites are generally in an unmethylated state. Methylation of CpG sites leads to changes in chromosome structure, inhibits the binding of the promoter to transcription factors, and causes gene silencing, resulting in loss of function. In other words, MGMT methylation suppresses MGMT activity, making tumor cells more sensitive to alkylating agents such as the chemotherapy drug temozolomide (TMZ). Studies have shown that TMZ is highly mutagenic, causing alkylation at the O⁶position of guanine. There exists a complex ‘triangular relationship’ among MGMT, TMZ, and tumor cells.

MGMT methylation is associated with the development of various tumors. In different glioma subtypes, the incidence of MGMT methylation varies significantly (Figure 1): 60-80% in oligodendroglioma, 20-45% in glioblastoma, 40-50% in anaplastic astrocytoma, and 20-30% in pilocytic astrocytoma. Based on multiple clinical trial results, the positive rate of MGMT methylation is close to 50%, while it is much lower in pediatric patients.

• Epigenetic inactivation of MGMT may contribute to inducing point mutations in TP53 and other oncogenes during tumorigenesis and tumor progression.

• In secondary glioblastoma and low-grade glioma, MGMT methylation is positively correlated with IDH mutation and 1p19q deletion status.

• MGMT promoter methylation is a favorable prognostic indicator for survival and can predict the sensitivity of glioblastoma and anaplastic astrocytoma to alkylating chemotherapy agents. However, for patients without IDH mutations, MGMT methylation does not have a predictive role.

• Glioma patients with hypermethylation of the MGMT gene promoter are more sensitive to chemoradiotherapy and have longer survival (Figure 2).

• Treatment decisions for elderly glioblastoma patients should prioritize the MGMT promoter methylation status.

• The level of MGMT promoter methylation in adult low-grade glioma can serve as a predictor for hypermutation at recurrence.

  
  

Figure 2 Correlation between MGMT protein expression and overall survival (OS) and progression-free survival (PFS) in glioma patients

Clinically, it is recommended that all high-grade gliomas undergo MGMT promoter methylation testing. Common methods for detecting MGMT methylation are mostly PCR-based. Multiple trials have shown that the concordance rate between PCR and IHC methods exceeds 83%. It is worth noting that the methylation status of the MGMT promoter is the main factor determining MGMT IHC expression levels. Therefore, in interpretation, patients with positive MGMT promoter methylation results from molecular testing correspond to negative clinical MGMT immunohistochemistry results.

References:

[1] Chinese Glioma Cooperative Group, Chinese Glioma Genome Atlas Project. Chinese guidelines for molecular diagnosis and treatment of glioma[J]. Chinese Journal of Neurosurgery, 2014, 30(5):435-444. DOI:10.3760/cma.j.issn.1001-2346.2014.05.002.

[2] Radhika M , Yalan Z , Grimmer M R , et al. MGMT promoter methylation level in newly diagnosed low-grade glioma is a predictor of hypermutation at recurrence[J]. 2020.

[2] Ogura R , Tsukamoto Y , Natsumeda M , et al. Immunohistochemical profiles of IDH1, MGMT and P53: practical significance for prognostication of patients with diffuse gliomas.[J]. Neuropathology Official Journal of the Japanese Society of Neuropathology, 2015, 35(4):324-335.

[2] Pandith A A , Qasim I , Zahoor W , et al. Concordant association validates MGMT methylation and protein expression as favorable prognostic factors in glioma patients on alkylating chemotherapy (Temozolomide)[J]. Scientific Reports, 2018, 8(1):6704.

[5] Bell E H , Zhang P , Fisher B J , et al. Association of MGMT Promoter Methylation Status With Survival Outcomes in Patients With High-Risk Glioma Treated With Radiotherapy and Temozolomide: An Analysis From the NRG Oncology/RTOG 0424 Trial[J]. JAMA Oncology, 2018, 4(10).