MGMT


MGMT stands for O6-methylguanine-DNA methyltransferase, which is a type of DNA repair protein. Its main job is to protect cells by fixing a specific kind of damage to DNA caused by chemicals called alkylating agents. These agents are sometimes used in chemotherapy to destroy cancer cells, but MGMT can repair this damage and make the treatment less effective. The MGMT gene, which provides instructions for making this protein, is found on chromosome 10.

What does MGMT do?

MGMT repairs damaged DNA by removing harmful chemical groups (called alkyl groups) from a specific part of the DNA. This prevents mutations that might lead to cancer. However, in cancer treatment, having a working MGMT gene can actually be a disadvantage because it may repair the very damage that chemotherapy is trying to cause in the cancer cells.

What does MGMT methylation mean?

Sometimes, the promoter region of the MGMT gene (the part that controls whether the gene is turned on or off) becomes methylated. Methylation is a natural chemical change that can silence or “turn off” a gene. When the MGMT promoter is methylated, the gene stops working and the MGMT protein is not made. This makes tumor cells less able to repair DNA damage caused by certain chemotherapy drugs like temozolomide, which can make these treatments more effective.

How do pathologists test for MGMT methylation?

Pathologists test for MGMT methylation using molecular tests that look at the promoter region of the MGMT gene. These tests are performed on tumor tissue and determine how much of the gene is methylated. The result is usually given as a percentage. A higher percentage means more methylation, and this can help predict how well a tumor might respond to certain types of chemotherapy.

A result with more than 10% methylation is usually considered positive for MGMT methylation, especially in tumors that are IDH-wildtype glioblastomas. Some pathologists may use a higher threshold, such as 30%, in other tumor types like IDH-mutant gliomas.

There are several types of tests used to measure MGMT methylation:

  • Methylation-specific PCR (MSP) – A common test that detects whether specific DNA sequences in the MGMT gene are methylated.

  • Quantitative methylation-specific PCR (MethyLight qMSP) – A more sensitive version that provides a percentage of methylation.

  • Pyrosequencing – A DNA sequencing method that can detect the exact pattern and percentage of methylation.

  • DNA methylation arrays – These advanced tests are sometimes used to help diagnose brain tumors and can also include MGMT methylation results.

The tests are usually done on formalin-fixed paraffin-embedded (FFPE) tissue or frozen tissue taken during surgery or biopsy. To ensure accurate results, the pathologist selects the area of the tumor with the highest number of viable cancer cells and avoids areas of dead tissue or surrounding normal brain.

What types of tumors show MGMT methylation?

MGMT promoter methylation is most commonly tested in brain tumors, especially high-grade gliomas. These include:

  • IDH-wildtype glioblastomas – About 40 to 50% show MGMT methylation.

  • IDH-mutant astrocytomas – Over 75% show methylation, though the test may be less helpful for predicting treatment response in these tumors.

  • Oligodendrogliomas – The majority show MGMT promoter methylation.

  • High-grade astrocytoma with piloid features – About 46% show MGMT methylation.

  • Diffuse hemispheric glioma (H3 G34 mutant) – May show MGMT methylation.

  • Primary central nervous system (CNS) lymphoma – Around 52% may show MGMT methylation.

MGMT testing is not routinely used in other types of cancers, although research is ongoing.

Why is MGMT methylation important in a pathology report?

MGMT methylation helps pathologists and doctors predict how a brain tumor might respond to alkylating chemotherapy drugs like temozolomide. Tumors with MGMT promoter methylation often respond better to these treatments and are associated with longer survival.

In older adults with glioblastoma, knowing the MGMT status is especially important. Studies have shown that patients with methylated MGMT who receive temozolomide do better than those who do not. Even when treated with radiation alone, MGMT methylated tumors tend to have a better outcome than unmethylated ones.

Is MGMT testing used in other cancers?

Right now, the value of MGMT testing is well-established only in cancers of the central nervous system. Although some studies have looked at MGMT in cancers like lung and colorectal cancer, its role outside of brain tumors is still being studied and is not routinely used in those settings.

Questions to ask your doctor

  • Was my tumor tested for MGMT promoter methylation?

  • What do my MGMT results mean?

  • Will this affect how my treatment is planned?

  • Are there any clinical trials for patients with MGMT methylated or unmethylated tumors?

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