What is genomic instability (microsatellite instability)? How is it related to Lynch syndrome?

Our body contains approximately 30 trillion cells. Every day, millions die and millions are produced by copying other cells. In this sense, our body is far more complex than the world’s most sophisticated factory. Approximately 2300 new cells are produced every second. The most critical moment in forming a new cell is unquestionably DNAreplication. The code of life is another name for DNA, consisting of 3 billion nucleotides in sequence. Errors can occur during replication, and meticulous mechanisms usually repair them. In Lynch syndrome, the subject of this article, genes responsible for DNA repair are defective, resulting in genomic instability (microsatellite instability = MSI) .

MSI is the formation of repeated faulty nucleotide sequences resulting from deficient DNA repair

Microsatellite formation:

DNA is copied by placing a matching nucleotide opposite each existing one—for example, thymine (T) opposite adenine (A), and guanine (G) opposite cytosine (C). When 3 billion nucleotides are paired during DNA replication, some errors, such as mismatches, may occur. DNA repair genes normally identify and repair them. In conditions such as Lynch syndrome, however, mismatches cannot be repaired, termed mismatch repair (MMR) deficiency. These unmatched DNA sequences, called microsatellites, repeat and accumulate, creating genomic instability.

MSI is classified in 3 forms: high, low and stable. Although it occurs to varying degrees in other cancers, such as uterine, stomach, ovarian, liver, brain and skin cancers, %90 of colon cancer patients with Lynch syndrome (LS) have high MSI. High MSI results from defects in more than 2 DNA repair genes.

A study involving approximately 7000 colon cancer patients found a better disease course (prognosis) in those with high MSI. The reason is unclear, but accumulating genetic errors and poor differentiation—limited resemblance to a normally mature cell—may make MSI-high tumors more recognizable to the immune system. Indeed, lymphocytes, key immune cells, were more abundant in MSI-high tumor tissue (tumor-infiltrating lymphocytes = TIL).

What are the characteristics of MSI-high colon tumors?

• The right colonis a more frequent site
• Poor differentiation (poorly differentiated)
• High mucinogen content
• More tumor-infiltrating immune cells (TIL)
• Less tendency to spread / metastasize .
• MSI-high tumors respond less to chemotherapy than conventional colon tumors. However, they respond better to new-generation immunotherapies (immune checkpoint inhibitors, such as PD-1-blocking drugs).

How is MSI detected?

MSI testing is based on identifying specific nucleotide sequences using PCR (polymerase chain reaction). In people with suspected LS, MSI testing is recommended to confirm diagnosis, predict the disease course and select treatment.