MLH1

MLH1 is a gene that produces a protein involved in DNA repair, specifically in a process called mismatch repair. This protein works closely with other mismatch repair proteins, including PMS2, MSH2, and MSH6, to detect and fix small errors that occur when DNA is copied in dividing cells. Together, these proteins play an important role in maintaining DNA stability and preventing mutations that could lead to cancer.

What types of cells and tissues normally express MLH1?

MLH1 protein is found in most cells throughout the body and is essential for normal DNA repair and cellular function. It is especially important in cells that divide frequently, as these cells are at higher risk of DNA replication errors. In a healthy cell, MLH1 is part of the cell’s natural mismatch repair system that fixes DNA errors, helping to prevent mutations that could lead to cancer.

What causes a cell to lose MLH1 expression?

Loss of MLH1 expression in a cell often occurs due to genetic or epigenetic changes that affect the MLH1 gene. Genetic changes, such as mutations in the MLH1 gene, can prevent the gene from producing a functional protein. These mutations can be inherited (germline) or acquired during a person’s life (somatic). Inherited mutations, often linked to Lynch syndrome, increase the risk of developing certain types of cancers and can be passed to family members. Acquired mutations, by contrast, are found only in the tumour cells and do not affect the person’s overall genetic makeup or family risk.

Another common cause of MLH1 loss, particularly in sporadic (non-hereditary) cancers, is epigenetic modification through MLH1 promoter hypermethylation. In this process, a chemical change (methylation) occurs in the promoter region of the MLH1 gene, which acts as a switch controlling gene expression. Hypermethylation silences the MLH1 gene, meaning it no longer produces the MLH1 protein, compromising the cell’s DNA repair ability. This type of gene silencing is considered a somatic change, occurring only in the tumour and not inherited by family members.

Understanding the cause of MLH1 loss is essential for determining whether the condition is related to an inherited cancer syndrome or sporadic cancer, helping to guide treatment and familial risk assessment.

What happens when MLH1 expression is lost?

When the MLH1 gene or protein function is lost, cells are more likely to accumulate DNA errors, which can lead to the development of tumours, especially in tissues that divide frequently, like those in the digestive system. Pathologists often assess MLH1 status in various tumours to understand their behaviour and guide treatment options.

Do any benign (noncancerous) conditions show loss of MLH1?

Loss of MLH1 expression is generally associated with malignant (cancerous) conditions, especially those with DNA mismatch repair deficiencies. Benign (noncancerous) conditions typically do not show MLH1 loss. MLH1 testing is mainly used to evaluate malignant tumours where a loss of DNA repair function is suspected, contributing to uncontrolled cell growth and cancer development. For this reason, the loss of this protein is considered a marker for malignancy rather than benign conditions.

What types of cancers are associated with loss of MLH1 expression?

Loss of MLH1 expression is commonly associated with certain types of cancers, particularly those related to Lynch syndrome.

Here are some types of cancers that may show loss of MLH1 expression:

• Colorectal cancer
• Endometrial (uterine) cancer
• Gastric (stomach) cancer
• Ovarian cancer
• Small intestine cancer
• Hepatobiliary cancers
• Urinary tract cancers
• Brain tumours

Loss of MLH1 in these tumour types can suggest a defect in the tumour’s ability to repair DNA, which may affect treatment and prognosis.

What does MLH1 promoter hypermethylation mean?

MLH1 promoter hypermethylation refers to a change where chemical groups called methyl groups attach to the promoter region (the “on/off” switch) of the MLH1 gene, turning it off. This hypermethylation prevents the gene from making its repair protein, leading to the loss of MLH1 expression in the tumour. Hypermethylation of MLH1 is common in sporadic (non-inherited) colorectal and endometrial cancers. Identifying MLH1 promoter hypermethylation can help distinguish between sporadic cancers and those related to Lynch syndrome, which guides both treatment and further genetic testing.

What is the difference between a germline and somatic mutation in MLH1?

Mutations in MLH1 can occur as either germline or somatic mutations. Germline mutations are inherited and present in all body cells from birth. A germline MLH1 mutation increases the risk of certain cancers and is commonly associated with Lynch syndrome, an inherited cancer syndrome. People with Lynch syndrome have a higher risk of cancers in the colon, uterus, and other organs.

On the other hand, somatic mutations are acquired during a person’s life and are only present in tumour cells, not in every cell of the body. This type of mutation is not inherited and does not increase the risk of cancer in other family members. Understanding whether an MLH1 mutation is germline or somatic is important for assessing inherited cancer risk and determining if other family members may also be at risk.

Why do pathologists test for MLH1?

MLH1 testing helps pathologists understand whether a tumour has lost its DNA repair function, which can influence how the tumour behaves and responds to treatment. Loss of MLH1 suggests that the tumour has a defect in DNA mismatch repair, a process crucial for fixing DNA errors. Detecting MLH1 loss can provide information about the tumour’s likely behaviour, prognosis, and possible treatment options, as tumours with DNA repair deficiencies may respond differently to specific therapies.

How do pathologists test for MLH1?

Pathologists typically begin testing for MLH1 in tumour samples using immunohistochemistry (IHC). In this test, special antibodies detect the presence of the MLH1 protein within cells. If the MLH1 protein is present, the cell will change colour in response to the antibody, allowing pathologists to confirm its presence under a microscope. Tumours showing a loss of MLH1 protein expression may appear lighter or unstained.

If MLH1 loss is identified through IHC, pathologists may perform additional molecular tests to understand the reason behind the protein loss. One common test checks for MLH1 promoter hypermethylation, a process where chemical changes silence the MLH1 gene. If hypermethylation is detected, it suggests the MLH1 loss is likely a somatic (acquired) change within the tumour, not related to an inherited condition. Alternatively, if no hypermethylation is found, it may prompt further genetic testing for a possible germline (inherited) mutation, which could indicate a genetic syndrome like Lynch syndrome.

Here’s an example of how a molecular pathology report might show an abnormal MLH1 result:

Test: MLH1 Promoter Hypermethylation Assay
Result: Positive for MLH1 promoter hypermethylation

Interpretation: The MLH1 gene promoter shows hypermethylation, indicating that MLH1 expression is likely silenced due to acquired (somatic) changes in the tumour. This result supports an MLH1-deficient cancer likely unrelated to an inherited syndrome.