by Dr. C.H. Weaver M.D. updated 2/2020

Microsatellite instability (MSI) is the condition of genetic hypermutability or a predisposition to mutations in cells that results from the bodies impaired DNA mismatch repair (MMR) mechanism.

DNA MMR is an essential function and the way the body naturally corrects errors that spontaneously occur during cell division associated DNA replication.

Mismatch Repair Genes work like genetic “spell checkers.” When problems occur in these spell-checking MMR genes, it means that areas of DNA start to become unstable and the body is unable to correct the errors that occur during DNA replication and consequently accumulate errors. The accumulation of errors causes the creation of novel microsatellite fragments that can be measured. The presence of MSI represents evidence that the MMR function is not working normally and predisposition to developing cancer exists.

Detection of MSI is important because MSI is a biomarker that identifies cancers more likely to respond to treatment with certain precision cancer medicines including PD-1 immune checkpoint inhibitors. PD-1 checkpoint inhibitors for example are very effective in treating advanced colorectal cancer with MSI-high (MSI-H. Doctors can use specific tests to detect for the presence of MSI.

What is MSI-H?

Microsatellite unstable cancers can be divided into two distinct MSI phenotypes: MSI-high (MSI-H) and MSI-low (MSI-L). MSI-H cancers are more likely to respond to certain treatments, especially with immunotherapy.

What causes MSI-H?

MSI-H is caused by the absence of certain proteins which help repair DNA in cells when it breaks. When these are absent or not working properly a healthy cell can’t repair itself normally and it starts making many mistakes in its own genetic code. This disordered repair and growth is the hallmark of cancer.

What are the common cancers associated with MSI-H status?

Colorectal cancer is the disease most commonly associated with MSI-H, but essentially any cancer can be implicated. MSI-H colon cancers are best treated with a certain type of immunotherapy called checkpoint inhibitors which are more effective than chemotherapy.

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Is MSI-H common?

Microsatellite Instability High (MSI-H) MSI-H is a DNA abnormality found in about 15% of colon cancers and other cancers. It is most often found in cancers associated with genetic syndromes like Lynch syndrome but can also occur sporadically. MSI-H is what “happens” when the genes that regulate DNA function don’t work correctly.

Why is it important to test for MSI-H status following a cancer diagnosis?

Since MSI-H is frequently associated with genetic deficiencies that can be hereditary, it is important to understand the implications for family members. MSI-H findings on a cancer can also be sporadic, meaning that they don’t always change a family member’s risk of developing the same types of cancer.

Deficiencies of the genes most frequently responsible for causing MSI-H cancers are most often associated with a syndrome called HNPCC or hereditary non-polyposis colorectal cancer syndrome. It is commonly referred to as Lynch syndrome. There are a number of other cancers involved in this syndrome including uterine, bile duct, stomach, pancreatic, bladder and small intestine cancer, among many others.

How does MSI-H status affect the immune system, for example, in the use of immunotherapies?

The immune system is more easily able to “recognize” MSI-H cancers, meaning that they respond far more readily to treatment with immunotherapy drugs.

What is MSI testing for colon cancer?

MSI and MMR testing: Colorectal cancer cells are typically tested to see if they show high levels of gene changes called microsatellite instability (MSI). Testing might also be done to see if the cancer cells have changes in any of the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2)