MLH1 promoter methylation


MLH1 promoter methylation is a change that affects the way the MLH1 gene is switched on and off. The MLH1 gene provides instructions for making a protein that repairs mistakes in DNA. When the promoter region of the gene (the “on–off switch”) becomes abnormally methylated, the MLH1 gene is turned off. As a result, the MLH1 protein is not made, and DNA errors can build up in cells.

This process is called an epigenetic change, because it affects how the gene works without changing the DNA sequence itself. Loss of MLH1 function can cause mismatch repair deficiency, which often leads to microsatellite instability (MSI), a feature commonly seen in colorectal and endometrial cancers.

Why is MLH1 promoter methylation important?

Testing for MLH1 promoter methylation is an important step when a tumor shows loss of MLH1 protein on immunohistochemistry. This test helps doctors determine whether the cancer developed because of a sporadic (non-inherited) change or whether it could be part of an inherited condition such as Lynch syndrome.

  • In sporadic cancers, MLH1 promoter methylation is usually the cause of MLH1 loss. This is seen in about 10–20% of colorectal cancers and up to 30% of endometrial cancers.

  • In Lynch syndrome, which is caused by inherited mutations in DNA repair genes, MLH1 promoter methylation is less common but can sometimes occur in addition to an inherited mutation. In these cases, it may act as a “second hit” that silences the gene.

Knowing whether MLH1 promoter methylation is present helps guide whether a patient should undergo genetic testing for Lynch syndrome.

How do doctors test for MLH1 promoter methylation?

Pathologists can test for MLH1 promoter methylation using several laboratory methods. These tests look for chemical “tags” called methyl groups on the promoter region of the MLH1 gene. Common approaches include:

  • Methylation-specific PCR (polymerase chain reaction): Detects methyl groups in specific parts of the MLH1 promoter.

  • Pyrosequencing: Measures the percentage of methylation at key DNA sites.

  • Array-based testing: Uses high-throughput methods to check many sites across the genome, including MLH1.

Results are usually reported as positive (hypermethylated) or negative (not methylated). A positive result means the MLH1 gene is turned off by methylation.

What does a positive MLH1 promoter methylation result mean?

  • If the tumor shows MLH1 methylation, it is usually considered sporadic and not related to inherited Lynch syndrome.

  • If the tumor does not show methylation but still has MLH1 loss, genetic testing for Lynch syndrome is often recommended.

  • Rarely, methylation can be found in people who also carry an inherited MLH1 mutation. In these cases, methylation may serve as the “second hit” that causes cancer to develop.

Questions to ask your doctor

  • Was my tumor tested for MLH1 promoter methylation?

  • What do the results mean for my risk of Lynch syndrome?

  • Do I need additional genetic testing?

  • How will this result affect my treatment plan or follow-up?

  • Should my family members be tested for inherited cancer risk?

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