Microsatellite Instability (MSI) as a Stomach Cancer Biomarker

A biomarker refers to any biological characteristic found in your tissues or bodily fluids that can be measured and evaluated objectively. Examples of biomarkers used in clinical practice include your blood pressure and heart rate.

Biomarkers serve as indicators of normal or abnormal processes, conditions or diseases, such as cancer. In oncology, biomarkers can come in the form of proteins, genetic material like DNA and RNA, and many other biological molecules derived from your blood, urine, saliva and tumor tissues.

These biomarkers are typically involved in the formation of cancer or are released due to the presence of the disease. Therefore, testing for cancer biomarkers in your blood or tissue samples can reveal important details about the cancer you’ve been diagnosed with.

Microsatellites are short, repeating sequences of DNA that are typically one to six nucleotides in length. Each unit or motif can be repeated five to 50 times in succession. These DNA segments are usually non-coding, which means they do not provide instructions for the production of any proteins. Microsatellite motifs can contain any combination of the four nucleotides (adenine, thymine, guanine and cytosine) and are scattered throughout your genome at thousands of locations.

Microsatellites are susceptible to having mismatch errors, which happens when nucleotides are incorrectly paired together during cell replication. In normal circumstances, these errors can be repaired by mismatch repair (MMR) proteins. MMR proteins act as “spell-checkers” that catch and correct errors in your DNA. However, if any of your MMR genes are mutated (changed or altered), their protein products lose their repairing function. This is known as a deficient MMR (dMMR) system, which allows DNA mismatches to accumulate in the microsatellite regions. This phenomenon is referred to as microsatellite instability (MSI). MSI can occur spontaneously or as a result of certain environmental factors, like exposure to radiation or chemicals.

An MMR deficiency and high MSI (MSI-H) can lead to mutations and the subsequent inactivation of downstream genes. These genes, such as tumor suppressors p53 and adenomatous polyposis coli (APC), are responsible for regulating cell growth and division. As a result of their inactivation, affected cells can start to divide uncontrollably and turn cancerous.

MSI is a biomarker associated with many cancers including colorectal and stomach (or gastric) cancer. Research has found that gastric tumors with high MSI typically express high levels of PD-L1, another gastric cancer biomarker.

Such tumors are notoriously capable of evading detection and attack by your immune system. They do so by making use of the interaction between PD-L1 and its partner protein, PD-1, which is found on the surface of T lymphocytes. When PD-L1 and PD-1 bind, this signals the T lymphocytes not to kill your gastric cancer cells, effectively turning off your body’s immune response towards the tumor.

Because of the link between MSI and PD-L1 overexpression, MSI is a predictive biomarker that can determine whether you will respond to immunotherapy using nivolumab and pembrolizumab. These are two drugs that target and block the PD-L1/PD-1 interaction, which would subsequently trigger an immune response to attack your gastric cancer cells.

More interestingly, evidence has shown that MSI-H tumors possess a better prognosis than MSI-low or MSI-negative tumors. This is because MSI-H tumors have a lower capacity of invading nearby tissues and spreading to surrounding lymph nodes.

For these reasons, MSI frequency has cemented itself as a major predictive and prognostic biomarker in gastric cancer. In light of its relevance, it is recommended for people with advanced or metastatic gastric cancer to undergo biomarker testing. This can help your doctors to determine your tumor’s MSI levels or if you carry a mutation in the MMR genes that cause MSI.

> Learn more about the types of biomarker tests performed for gastric cancer