How Microsatellite Instability Works in Colorectal Cancer

Understanding one’s biomarkers, such as microsatellite stable (MSS) or instable (MSI) status in tumors, is key in understanding how a patient with colorectal cancer may be treated.

In a breakout session at the 3rd Annual GI Cancer Patient Summit — hosted by Hope Connections for Cancer Support and The Ruesch Center for the Cure of Gastrointestinal Cancers at Georgetown Lombardi Comprehensive Cancer Center – John Marshall, M.D., and Donald B. Colvin, M.D., FACS, FASCRS, explained how exactly this works.

“All colorectal cancers must know their MSS or MSI biomarker status. That is where you have the inherited kind (of the disease), but it doesn’t necessarily have to come from your parents, you can acquire this (biomarker),” explained Marshall, who is chief of the division of hematology/oncology at Medstar Georgetown University Hospital and director of the Otto J. Ruesch Center for the Cure of Gastrointestinal Cancer.

“The MSI group is the group where the immune therapies are working, not perfectly, but they are working,” he added. “In the MSS group, which is most everybody, they don’t work so well.”

MSI status means there is a high amount of instability in a tumor, which occurs as a result of when genes that regulate DNA, also called mismatch repair (MMR) genes, do not correct errors in DNA as the cancer cells divide. MMR genes work similar to “spell checkers” looking for a typo; however, in instances of MSI tumors, those “spell checkers” are broken, Marshall said.

“When the DNA damage happens (in an MSI tumor), it doesn’t get fixed,” he added. “So, a typical colon cancer cell that is MSI, may in fact have thousands of mutations; whereas, an MSS tumor only has 100 mutations. And the belief is that each one of those mutations (is different).”

These mutations and the MSI biomarker come in to play with immunotherapy treatment and how the immune system and its T cells — a type of white blood cell that tailors the body's immune response to specific pathogens – recognize these tumors.

“Some tumors have the ability to cloak themselves and be recognized as cells, so the T cell isn’t activated and can’t discover it. That’s how the body normally recognizes these cells, because of those checkpoints,” explained Colvin, who is the founder of Fairfax Colon & Rectal Surgery and associate professor of surgery for the Medical College of Virginia.

“And if the tumor disguises itself, or cloaks itself, then the immune system can’t recognize it to attack it.”

However, in MSI tumors, because these DNA cells are being broken into thousands of mutations, the immune system can recognize these peptides to kill them. To help patients understand, Marshall compared this process to Star Wars.

“The planet (your tumor) is being protected by the evil Darth Vader, and what you have to do to get Luke Skywalker (the T cell) in to the planet is to break down this forcefield (checkpoint pathways),” he explained. “The T cell is prevented from getting in because of this checkpoint, this forcefield. And (checkpoint inhibitors like PD-1 and PD-L1) take it out.”

“Nothing happens to your immune system and nothing happens to your tumor,” Marshall added. “The T cell is already there and ready to go and can now kill (the cancer cells).”