There are as many different cancers as there are people with cancer. Unlike infectious diseases, which are caused by pathogens that are foreign to our bodies (bacteria, viruses, parasites), cancer cells arise from our body—our own cells gone rogue. Because cancer is a dysfunction of a person’s normal cells, every cancer reflects the genetic differences that mark us as individuals. Add to that environmental influences like diet, tobacco use, the microbiome and even occupation, and the likelihood of finding a “single” pharmaceutical cure for cancer becomes virtually impossible.
But, while looking for a single cure for all cancers may not be a fruitful activity, defining a best practice for understanding the genetic and protein biomarkers of individual tumors is proving worthwhile.
One of the most well understood cancers for which individualized treatments based on tumor biomarkers have been successful is breast cancer. Testing breast tumors for the abnormal expression of certain hormone receptor proteins that are on the cell surface [estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor 2 (HER2)] helps define the treatment for those tumors.
Another marker that is useful in directing cancer treatment is the genetic marker of Microsatellite Instability or (MSI). MSI testing measures the ability of a cell to repair mistakes in DNA replication. Every time a cell divides, the DNA of that cell is copied. And just like writers and editors can make copy/paste errors when copying text, the machinery of the cell sometimes makes mistakes when copying the DNA before cell division. One of these errors is called mismatch, when extra nucleotides are inserted into or deleted from the newly synthesized strand of DNA and there are no corresponding matches on the template strand. Normal cells have a system, called mismatch repair, to detect and correct such errors. Certain parts of the genome called microsatellites are particularly sensitive to mismatch errors and serve as markers of mismatch repair deficiency (dMMR)—or situations in which the normal mismatch repair mechanisms are not functioning well.
Mismatch repair problems are an issue with tumors because tumors divide rapidly, creating many opportunities for DNA copy errors. Some people with a genetic condition, known as Lynch Syndrome, have inherited mutations that affect the mismatch repair system which places them at higher risk to develop certain cancers than people with a normally functioning mismatch repair system. But, even if an individual does not have Lynch Syndrome, certain kinds of solid tumor cells can acquire mutations that affect their ability to repair mismatch copy errors. When this happens, those tumor cells show increased microsatellite instability, or are said to be MSI-High.
MSI screening can be used to characterize tumors and guide therapeutic choices for MSI-High cancer types. Tumors with MSI-High status have been shown to respond to immune checkpoint inhibitor (ICI) therapies. Tumors with defects in the expression of functional MMR (dMMR) proteins often have somatic mutations that produce “foreign” proteins that can be detected by the immune system. As a result, these tumors are effective at priming an immune response and subsequently susceptible to immunotherapies. Because MSI can be the first evidence of an MMR deficiency, MSI-High status is predictive of a positive response to immunotherapies such as immune checkpoint blockade inhibitors.
Promega Corporation recently announced a global collaboration with Merck to develop the Promega microsatellite instability (MSI) technology as an on-label, solid tumor companion diagnostic (CDx) for use with Merck’s immune checkpoint anti-PD-1 therapy, KEYTRUDA® (pembrolizumab).
Promega’s research use MSI technology has been validated in labs around the world to characterize solid tumor MSI status. As scientists understand more about the biology of MSI-high tumor cells, even more tailored and effective therapies can be developed against tumors expressing the MSI biomarker.
For Further Reading
- Villanueva, J. (2018) Life with Lynch Syndrome. Promega Corporation.
- Villanueva, J. (2018) Dreaming of Universal Tumor Screening. Promega Corporation.
- Boland, C.R. and Lynch, H.T. The History of Lynch Syndrome. Familial Cancer. 12(2): 145–157.
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