Research
Association of MGMT status with survival in low and high-grade IDH-mutant astrocytomas.
Background
MGMT is one of the key genes associated with tumour progression and drug resistance. In short, it is an example of a Tumour Suppressor Gene — a class of genes that, when active, prevent cells from becoming malignant. MGMT encodes a protein responsible for repairing DNA, decreasing the probability of cells acquiring mutations that may lead to tumour progression.
All genes are subject to regulation: there are many mechanisms ensuring that correct genes are active in the right place and at the right time. Promoter methylation is one of these mechanisms: by chemically modifying (methylating) the part of the gene most responsible for activity (the promoter), a gene can be down-regulated, meaning made less active. This is a normal process occurring in all cells; however, malignant cells very commonly use this mechanism to turn off the Tumour Suppressor Genes.[1]
To summarise, by MGMT promoter methylation status we mean whether the Tumour Suppressor Gene MGMT is “turned off” by a process called promoter methylation.
Specifically, Low-Grade Gliomas often display a “Glioma-Associated CpG Island Methylator Phenotype” (G-CIMP), which means their cells turn off many genes through methylation. This is a result of their IDH mutation.[2] This characteristic is clinically relevant, as it may help predict the course of the disease and inform treatment. For example, the current standard of care, Temozolomide, works by inducing DNA damage, which means that it might be more effective against tumours with deactivated DNA repair genes.
The methods
The authors (Schwetye et al., 2025) investigated the relation between the methylation of MGMT (whether this gene was turned off or not) and survival in patients with IDH-mutant astrocytoma or glioblastoma. The authors used pyrosequencing, which is a method of identifying methylation in the DNA, to analyse the MGMT status in patients, and investigated how this relates to the overall survival, and how this is influenced by other factors such as age, gender, and treatment type.
The results
The authors found that glioblastoma patients with methylated (deactivated) MGMT gene had better overall survival chances (Hazard Ratio, HR = 0.62, meaning that patients with MGMT methylation had a 38% reduced risk of death over the course of the study). This effect was increased by Temozolomide (TMZ) chemotherapy (HR=0.53).
This effect was not observed in lower- or higher-grade astrocytoma: it seems that MGMT methylation might not have a significant impact on overall survival in this disease, nor on the response to Temozolomide. This does not, however, mean that MGMT methylation won’t impact the effectiveness of other therapeutics.
The relations between MGMT methylation and other genetic markers were investigated. Astrocytomas harbour mutations in the ATRX gene, which is strongly associated with changes in the activity of other genes (called epigenomic dysregulation). Mutations in this gene were more common in second and third grade astrocytomas with MGMT methylation, likely meaning that a mutation in ATRX can lead to MGMT methylation. The SETD2 gene mutation, which occurs specifically in high grade gliomas in young patients, was more prevalent when the MGMT gene was not methylated in lower-grade (second and third grade) astrocytomas. In high grade (grade 4) astrocytomas and glioblastomas, the presence of MGMT methylation was associated with a higher number of mutations, as indicated by tumour mutational burden.
Conclusion
The authors have found that while MGMT methylation status, which impacts the DNA repair capabilities of tumours, has a pronounced impact on the effectiveness of therapy in glioblastoma patients, it was not found to influence the outcomes of astrocytoma patients.
Specifically, glioblastoma with MGMT methylation present was associated with improved survival and better response to Temozolomide therapy in comparison with unmethylated MGMT glioblastoma.
Personally, I would interpret this result as highlighting that astrocytoma and glioblastoma are biologically different, and different genes are relevant for predicting the course of the disease and response to therapy. The fact that lower- and higher-grade astrocytomas with MGMT methylation present did not respond to Temozolomide better than lower- and higher-grade astrocytomas without MGMT methylation might indicate that these tumours have other drug-resistance mechanisms against alkylating chemotherapy (a type of chemotherapy that damages DNA by inducing chemical changes, such as Temozolomide).
Piotr Skubis,
Morse Lab at Imperial College London
- Weinberg’s “The Biology of Cancer” describes this phenomenon very well in Chapter 7: Tumour Suppressor Genes.↩︎
- As described in the WHO 2021 Classification of Central Nervous System Tumours.↩︎