PMS2 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 MLH1, 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.
PMS2 protein is found in nearly all cells in the body, particularly in tissues with rapidly dividing cells, such as those in the digestive system. It plays a vital role in the body’s natural repair mechanisms to keep DNA accurate and functional, helping protect cells from accumulating mutations. Its expression is necessary for normal cell function and DNA repair across various tissue types.
Loss of PMS2 expression can happen due to mutations in the PMS2 gene itself, which can be either inherited (germline) or acquired (somatic). Inherited mutations can lead to a condition known as Lynch syndrome, which significantly increases the risk of certain cancers. Somatic mutations, on the other hand, occur in tumour cells during a person’s lifetime and are not inherited or passed to family members. Additionally, loss of PMS2 expression may occur due to epigenetic changes, which affect how the gene functions without altering the DNA sequence. These changes can silence the gene, meaning it’s not expressed even though the DNA sequence remains unchanged, leading to a deficiency in the mismatch repair system.
When PMS2 is lost, cells are less able to repair DNA errors effectively, increasing the likelihood of mutations that could lead to tumour development. A loss of PMS2 function is often associated with certain types of cancers and may suggest a DNA repair deficiency in the tumour cells. Testing for PMS2 expression in tumour samples can help pathologists understand the tumour’s behaviour and may inform treatment options.
Loss of PMS2 expression is often found in several types of cancers, especially those associated with Lynch syndrome, a hereditary cancer condition.
Cancers that may show loss of PMS2 expression include:
In these cancers, the loss of PMS2 can indicate a DNA repair defect, which may impact prognosis and inform specific treatment approaches.
Loss of PMS2 expression is generally associated with malignant (cancerous) conditions rather than benign (noncancerous) conditions. Benign conditions usually retain PMS2 function, as they do not typically have the high mutation rates seen in cancers.
Mutations in PMS2 can be either germline or somatic. Germline mutations are inherited and present in all cells of the body from birth, increasing the risk of certain cancers, particularly those related to Lynch syndrome. People with Lynch syndrome have a higher risk of cancers in organs like the colon and uterus.
Somatic mutations, on the other hand, are acquired during a person’s life and are only present in tumour cells, not all body cells. Somatic mutations are not inherited and do not increase cancer risk for other family members. Knowing if a PMS2 mutation is germline or somatic helps assess inherited cancer risk and determine if family members may also be at risk.
Testing for PMS2 helps pathologists determine whether a tumour has lost its DNA repair ability, which could influence the tumour’s growth and response to treatment. Loss of PMS2 often suggests a defect in DNA mismatch repair, which is important for correcting DNA errors. This information can help pathologists predict how the tumour might behave, its prognosis, and any specific treatment options, as tumours with DNA repair deficiencies may respond differently to particular therapies.
Pathologists generally start by testing for PMS2 protein in tumour tissue samples using immunohistochemistry (IHC). This test uses antibodies that bind to the PMS2 protein if it is present in the cells. When the PMS2 protein is detected, it produces a visible colour change under a microscope. Tumours that lack PMS2 protein will appear lighter or unstained in the test.
If a loss of PMS2 is identified through IHC, pathologists may then consider further genetic testing to see if a germline (inherited) mutation is present. This testing is typically done on a blood sample to determine if the mutation is related to Lynch syndrome, which would suggest a higher cancer risk for the patient and potentially their family members.
The most common genetic syndrome associated with PMS2 is Lynch syndrome, an inherited condition that increases the risk of several cancers, particularly colorectal and endometrial cancers. Lynch syndrome occurs when a person inherits a germline mutation in one of the mismatch repair genes, including PMS2. This syndrome has a high risk of causing cancers in various organs and is important to identify for the health of both the patient and family members.
To test for genetic syndromes like Lynch syndrome, pathologists often perform genetic testing on a blood sample to look for germline mutations in the PMS2 gene. This testing can help determine if the patient has an inherited mutation that would increase their risk for Lynch syndrome-associated cancers.
Here’s an example of how a molecular pathology report might show an abnormal PMS2 result:
Test: PMS2 Genetic Mutation Analysis
Result: Positive for germline PMS2 mutation
Interpretation: The PMS2 gene shows a germline mutation, indicating a likely hereditary risk for Lynch syndrome. This result suggests an increased risk for Lynch syndrome-associated cancers, such as colorectal and endometrial cancer. Testing for Lynch syndrome in family members may be advised.
This testing helps clarify whether the loss of PMS2 is likely due to a genetic syndrome or an acquired change within the tumour cells.