What Is Microsatellite Instability? What Does DNA Mismatch Repair Mean?

Microsatellite instability, DNA mismatch repair deficiency (DNA mistmach repair deficiency) and genomic instability are closely related terms that are sometimes used interchangeably.

Genomic instability results from insufficient repair of DNA mismatches. Why do mismatches occur in DNA, and why can they sometimes not be repaired?

Our bodies contain approximately 30 trillion cells. Each day, of every 300 cells, one is estimated to multiply through mitotic division . An equal number undergo programmed death (apoptosis). Producing 100 billion new cells daily, our bodies are far more complex than the world’s most complex factory. The most critical moment in forming a new cell is undoubtedly copying DNA. Also called the code of life, our DNA consists of 3 billion nucleotides arranged in sequence. During copying, errors (mutations) can occur, although very rarely. Even if mutations occur only once in a million cell divisions—remembering the 100 billion daily divisions—that means 100 thousand mutations daily. These are mostly corrected by meticulous DNA repair systems. When DNA damage cannot be repaired and errors accumulate, cancer development is triggered.

The DNA mismatch repair system is one of the mechanisms cells use to repair DNA damage, medically called DNA mistmach repair. Mutations in genes encoding this repair system cause DNA mismatch repair deficiency , leading to accumulation of mismatched DNA sequences called microsatellites . The result is genomic instability.

DNA mismatch repair deficiency produces DNA mistmach repair deficient (dMMR), or microsatellite instability-high (MSI-H), tumors.

Microsatellite formation: DNA is copied by placing a matching nucleotide opposite each nucleotide (for example, thymine (T) opposite adenine (A), and guanine (G) opposite cytosine (C)). Copying DNA involves pairing 3 billion nucleotides, during which errors such as mismatches can occur. Normally, DNA mismatch repair enzymes detect and correct these. However, mutations in genes encoding the enzymes prevent repair, allowing faulty DNA sequences called microsatellites to accumulate and create genomic instability.

This has been studied extensively in colorectal (large bowel) cancers. Approximately 4% of all colon cancers are microsatellite instability-high (MSI-H) tumors. Identifying them is important because they respond well to immunotherapy drugs . Because these tumors respond well, microsatellite instability has recently entered cancer medicine as a valuable biomarker.

A study involving approximately 7000 colorectal cancer patients found a better prognosis (disease outlook) in those with MSI-H tumors. Although the reason is unclear, accumulated genetic errors may make these tumors more recognizable to the immune system. Indeed, MSI-high tumor tissue contained higher concentrations of lymphocytes, key immune cells.

What are the characteristics of MSI-high colon tumors?

• More commonly located in the right colon
• Poor differentiation (poorly differentiated)
• High mucinogen content
• More tumor-infiltrating immune cells ((tumor infiltrating lymphocytes = TIL)
• Metastasis is less likely
• MSI-high tumors respond less to chemotherapy than conventional colon tumors. However, they respond better to next-generation immunotherapies (immune checkpoint inhibitors, such as drugs blocking PD-1 and PD-L1).

How is MSI detected?

MSI testing is based on detecting specific nucleotide sequences using PCR (polymerase chain reaction). Particularly in stage 4 colon cancer, MSI testing is recommended both to predict disease course and select patients likely to benefit from immunotherapy.

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