MSI-H/dMMR Biomarker

Microsatellites are repetitive short regions of DNA throughout the genome. The genome is the complete set of DNA – you can think of it like a book with all the “instructions” to make you who you are. Microsatellites vary in size and patterns. It may be helpful to think of these microsatellite regions as the “fingerprint” of DNA, as individuals have unique microsatellite regions. These regions serve as a biomarker.

A microsatellite repeat is when this specific sequence of DNA (or microsatellite) is repeated. For example, if we think of a microsatellite as a word, a microsatellite repeat would be if the same word was written multiple times or repeatedly in the same sentence.

Microsatellite stability is a measure of DNA stability and it is determined by comparing the number of microsatellite repeats in healthy cells and in cancer cells. If all cells in the body have an equal number of microsatellite repeats, this is classified as being as microsatellite stable (MSS). Sometimes cancer cells acquire too many or too few microsatellite repeats compared to healthy cells, and this is a biomarker for high microsatellite instability (MSI-H).

In healthy cells, DNA mismatch repair (MMR) genes act as a quality control mechanism to “spell check” DNA for errors. However, cancer cells may become deficient in mismatch repair (dMMR). Cancer cells that are dMMR have difficulty repairing mistakes or mutations in DNA. Microsatellite regions are prone to mutations due to their repeating sequence. As a result of dMMR, cancer cells will have too many or too few microsatellite repeats compared to healthy cells and these cancer cells are considered MSI-H/dMMR.

MSI testing is recommended for all colorectal cancer patients. Talk to your surgeon or oncologist about MSI testing. MSI testing is usually performed using a biopsy or tissue taken during surgery.

Polymerase chain reaction (PCR) is often used for MSI testing. MSI testing looks at the length of specific DNA microsatellites from the tumor sample and compares them to healthy cells.

Alternatively, immunohistochemistry (IHC), which is a type of stain or dye applied to a slide made from a piece of the tumor, can be used to detect the presence or absence of MMR proteins.

The best way to ensure your tumor has been tested for MSI-H is to ask your medical care provider. A pathology report that examined MMR status will likely mention the following specific MMR proteins: MLH1, MSH2, MSH6, and PMS2. Absence of one or more of these proteins in a tumor sample are indicative of dMMR and MSI-H.

MSI-H tumors make up about 15% of all colorectal cancers and about 4% of stage IV colorectal cancers. After surgery, immunotherapy is often the preferred treatment option for dMMR/MSI-H colorectal cancer.

MSI-H cancer cells behave abnormally when compared to healthy cells, or even MSS or MSI-Low cancer cells. These abnormalities do offer some “advantages” when considering treatments. There is a high chance of a successful response to surgery for patients with localized, MSI-H colorectal cancers. Additionally, the abnormalities make it easier for the immune system to detect and destroy the cancer cells, making them sensitive to immunotherapies. These abnormalities also make the cancer cells act less aggressively, making them less likely to metastasize or spread, at least in the earlier stages of the cancer.

There are currently three FDA-approved immunotherapies for MSI-H colorectal cancer: pembrolizumab, nivolumab, and ipilimumab.

Pembrolizumab has been approved for the treatment of MSI-H colorectal cancers that previously received 5-FU, oxaliplatin, and irinotecan-based therapy OR treatment-naïve patients with metastatic MSI-H colorectal cancer. Nivolumab or a combination of nivolumab and ipilimumab has been approved for the treatment of MSI-H colorectal cancer that previously received 5-FU, oxaliplatin, and irinotecan-based therapy.

The most effective treatment for MSI-H colorectal cancer varies by individual. It is ideal to speak with your medical team to learn more about the best treatment options for you.

The majority (about 85%) of colorectal cancers are NOT MSI-H. If all cells in the body have an equal number of microsatellite repeats, this is referred to as microsatellite stable (MSS). You may also see this referred to as pMMR, or mismatch repair proficient. Patients with MSS colorectal cancer should consider further biomarker testing to help guide their treatment decisions.

The majority of patients with MSI-H tumors do not have an inherited predisposition to cancer. However, a subset of MSI-H tumors are hereditary, and this predisposition is often associated with an inherited condition known as Lynch syndrome.

When a tumor tests positive for MSI-H it does not necessarily mean you have Lynch syndrome. While MSI is a hallmark of Lynch syndrome, only a small subset (about 5%) of MSI-H colorectal cancers are a result of Lynch syndrome. If your tumor is positive for MSI-H, additional tests will be performed to look for inherited mutations. This involves testing some of your body’s cells, often from a blood draw or swab of the inside of the cheek to see if your own cells have the same MSI-H finding as the tumor cells have. First-degree relatives of patients diagnosed with Lynch syndrome should discuss genetic testing with their doctor.

Furthermore, MSI-H is also a hallmark of other inherited cancer predisposition syndromes.

Check out Fight CRC’s Clinical Trial Finder to search for trials for MSI-H patients and read our Clinical Trials Conversations for insights on important trials.