This article is about microsatellite instability. If you’re looking for microsatellite stability, click here.
What is the microsatellite instability biomarker?
The microsatellite instability (or microsatellite instability-high) biomarker gives information about how your cells handle errors that happen during cell processes.
During organ and tissue growth, or healing of organ and tissue damage, your cells divide to make more cells. As each cell splits, the DNA divides and makes a copy of itself for the new cells. This is called DNA replication. Mistakes that occur in the copying process are called DNA mismatches. The microsatellite stability status tells whether your cells can fix these mistakes. This is called DNA mismatch repair (MMR).
DNA mismatch repair is controlled by several genes, including MLH1, MSH2, MSH3, MSH6, MLH2, MLH3, PMS1, PMS2, and EPCAM. Mutations in these genes can cause mismatch repair deficiency. Germline mutations (inherited mutations) in these genes cause Lynch Syndrome, a hereditary colorectal cancer syndrome. In addition to mutations, there are other processes that affect gene and protein expression (phenotype), such as DNA hypermethylation. These processes, called epigenetic processes, can also cause mismatch repair deficiency. These types of changes are not usually inherited.
Microsatellites are small, repetitive segments of genomic DNA. MSI testing looks at whether these DNA segments have many mutations or few mutations. Mismatch repair status can also be tested by looking at the expression level of mismatch repair genes and proteins.
MSI status is both a prognostic and a predictive biomarker. It gives information about the usual course of disease (prognosis) and it predicts which treatments may be more or less effective against a particular colorectal cancer, such as conventional chemotherapy drugs or immune checkpoint blockade with immunotherapy drugs.
What is the difference between microsatellite instability and microsatellite stability?
Microsatellite instability and microsatellite stability are the two opposite results of the same biomarker test.
When the microsatellite DNA segments in your cancer cells show changes (mutations), this indicates that the tumor cells are deficient in the DNA repair of mismatch errors. These colorectal tumors have microsatellite instability (also called MSI-High, MSI-H, or mismatch repair deficiency, dMMR). MSI tumors may have abnormal levels of mismatch repair gene and protein expression due to mutation or epigenetic processes.
When microsatellite DNA segments are unchanged (not mutated) in your colorectal cancer, the tumor (tumour) cells are considered microsatellite stable (MSS). MSS colorectal cancers have normal levels of mismatch repair gene and mismatch repair protein expression. Microsatellite stable cancer cells are able correct DNA mismatch repair errors proficiently.
How is the microsatellite instability biomarker tested?
Microsatellite instability (and microsatellite stability) are measured in a biopsy sample of your colorectal cancer (CRC). There are several laboratory methods that can be used, including immunohistochemistry (IHC), polymerase chain reaction (PCR), and next-generation sequencing (NGS).
When tumor tissue is not available, microsatellite instability and stability can be measured in circulating tumor DNA (ctDNA). ctDNA is fragmented DNA released by your cancer cells into the blood. ctDNA can be isolated from a blood sample for testing. This is also known as liquid biopsy.
How are the results of microsatellite instability testing reported?
There are two possible results for this test, but there are several terms used interchangeably for each.
The microsatellite instability result may be reported as
- Microsatellite instability (MSI)
- Microsatellite instability-high (MSI-High, MSI-H)
- Deficient mismatch repair (dMMR)
The microsatellite stable result may be reported as
- Microsatellite stable (MSS)
- Microsatellite stability (MSS)
- Proficient mismatch repair (pMMR)
If your test result is microsatellite stability (MSS), please visit microsatellite stability.
What does my microsatellite instability result mean?
If your colorectal cancer has the MSI-High biomarker, this means that your tumor cells are unable to fix DNA mismatch mistakes. Your cancer cells have deficient mismatch repair (dMMR).
- MSI-High occurs in about 15% of colorectal cancers.
- dMMR is less common in stage IV / metastatic colon cancer or rectal cancer.
- Patients with MSI-High have a better overall prognosis than patients with MSS.
If you have MSI-High, you need to be tested for Lynch Syndrome. Also known as Hereditary Nonpolyposis Colorectal Cancer (HNPCC), Lynch Syndrome occurs in 3-5% of patients with MSI-High. It is caused by a hereditary mutation in one of the MMR genes which include MLH1, MSH2, MSH3, MSH6, MLH2, MLH3, PMS1, and PMS2. These patients are at increased risk for developing non-colorectal cancers too, including endometrial cancer (uterine cancer), gastric cancer (stomach cancer), and ovarian cancer. Biological relatives (siblings, children, cousins) of patients with Lynch Syndrome are at risk of having MMR gene mutations and Lynch Syndrome too. These family members should have genetic testing to determine if they are at increased risk so they can begin colorectal cancer screening and prevention at a younger age as well as have screening and preventive care for other Lynch Syndrome associated cancers.
How does the microsatellite instability biomarker result impact my treatment options?
- Fluorouracil-based chemotherapy (for example, 5-FU, FOLFOX, FOLFIRI) is less effective in patients with MSI-High.
- Immunotherapy with immune checkpoint inhibitors, such as pembrolizumab (Keytruda), nivolumab (Opdivo), and ipilimumab (Yervoy), is effective against colorectal cancers with MSI-High.
- Immune checkpoint inhibitors use your own immune system to kill cancer cells by promoting stronger responses against cancer cells from white blood cells in your tumor (tumor-infiltrating lymphocytes)
There are ongoing clinical trials of new drug combinations, including immune checkpoint inhibitors and other targeted therapies, to treat MSI-H and dMMR colorectal cancer. To learn more about clinical trials and how you can benefit, click here and talk to your oncology team.
Who should have microsatellite instability testing? When should MSI testing be performed?
All colorectal cancer (bowel cancer) patients should have testing for microsatellite instability and microsatellite stability at the time of their diagnosis. It does not matter what stage you are at diagnosis, whether you have stage I, stage II, stage III, or metastatic colorectal cancer, microsatellite instability status should always be tested. If you have not been tested, or are unsure if you have had MSI testing, please talk to your healthcare team.
If your test result is microsatellite instability (MSI, MSI-High, or dMMR), you will need testing for Lynch Syndrome, a hereditary cancer syndrome caused by deficient DNA mismatch repair.