DNA "autocorrect" provides precious cancer clues

A mechanism known as mismatch repair constantly scans our DNA, protecting cells from errors that cause disease. This biological workhorse is capturing the spotlight in its utility in the fight against cancer.

In each of us lives a rather remarkable system known as mismatch repair. This naturally occurring machinery works around the clock to vigilantly scan our DNA, searching for errors in replication. When defects are found, mismatch repair - or MMR - goes to work to correct them, preventing future health problems, like cancer.

Think of it as autocorrect for our DNA.

When this mechanism goes awry and cancer cells grow, MMR biomarkers in these cells can provide valuable clues on how to best treat the disease. 

In April 2021, Roche Diagnostics received U.S. Food and Drug Administration approval for the first companion diagnostic test based on MMR biomarkers to determine which endometrial cancer patients are eligible for immunotherapy. And this may just be the beginning, as approval for the test is expected to expand to additional cancer types and therapies.

Identifying patients likely to benefit from immunotherapy, which is treatment that stimulates the body’s immune system to attack and kill cancer cells, is a powerful tool in the fight against this disease.  

“I think this new mismatch repair test will remain important for the foreseeable future as we continue to learn more about immunotherapy,” says Dr. Eric Walk, a former Chief Medical and Scientific Officer at Roche Diagnostics.

“Immunotherapy in oncology has already caused a revolution in how we treat cancer, but I think the revolution has only just begun,” Eric adds. Roche is partnering with global pharmaceutical companies to explore combinations of treatments and combinations of biomarkers - including MMR - with the goal of increasing survival for patients. 

“Right now with cancer immunotherapy, we can bring durable benefit to about 20 percent of patients,” Eric says. “What we all want is to raise that level of benefit to 30, 40, 50 percent and ultimately 80, 90, 100 percent. To get there, we need more immunotherapies and more biomarkers to pinpoint treatment. I think MMR will be a very important biomarker in this effort.”

Dr. Eric Walk
MMR in the spotlight

A defect in the MMR mechanism has been associated with both hereditary tumors - such as Lynch syndrome, a form of colorectal cancer -  as well as sporadic tumors that occur in people with no family history.

MMR consists of four proteins called MLH1, MSH2, MSH6 and PMS2. Roche has had these four MMR biomarkers in its testing portfolio for decades, but only in recent years have they captured the spotlight in their utility in the fight against cancer.

In the early days, the four markers were used not to detect or predict disease, but as research tools to identify whether the proteins were working. 

Once it was determined that MMR biomarkers could help differentiate between sporadic colorectal cancer and Lynch syndrome, medical guidelines recommended universal screening of  all newly diagnosed cases of colorectal cancer. Identification of probable Lynch syndrome allowed clinicians to recommend additional testing and genetic counseling to patients and at-risk family members, with the goal of reducing disease and death. Working closely with the FDA, Roche launched an MMR screening test for Lynch syndrome in 2017.

Since then, the test has been investigated as a companion diagnostic to help identify which patients, based on biomarker status, would be eligible for immunotherapy in a variety of cancer types. It turns out that patients with MMR deficiency - meaning the ‘autocorrection’ isn’t working properly - are more likely to respond to immunotherapy.

“When I first saw the research, it didn’t make sense,” Eric says. “Why would someone with a defect in this autocorrection machinery have a better response to immunotherapy? Why would it be a good thing to have a defect in MMR? But the more I thought about how immunotherapy works, it started to make sense.”

"It’s like a tag on cancer cells that the immune system can latch on to and use to eliminate these cells. If we then activate the immune system with an immunotherapy drug, that's how we’re ultimately going to cure cancer."

MMR DNA strand

MMR and beyond: How to cure cancer

When MMR is deficient, it is not correcting errors in DNA. When errors are not fixed, cells mutate at a greater level, so cancer in a person with deficient MMR will have many more mutated proteins than in someone without this defect. Some of these neoantigens, as they are called, are seen as foreign by the immune system, enabling it to recognize and attack cancer with the aid of immunotherapy.

“It’s like a tag on cancer cells that the immune system can latch on to and use to eliminate these  cells. If we then activate the immune system with an immunotherapy drug, that's how we’re ultimately going to cure cancer,” Eric says. 

MMR is one of many biomarkers being studied in the setting of cancer immunotherapy and it may ultimately require a combination approach to match patients with the best treatments.

The need to visualize multiple biomarkers makes tools like multiplexing - where pathologists can see several cancer biomarkers on a single tissue slide - and digital pathology a must-have, Eric says.

“Once you get into four and five different biomarkers on one slide, the ability of a human to track and understand these streams of data and quantify them accurately becomes impossible. We need automated image analysis, artificial intelligence and machine learning algorithms. We'll need to embed these digital tools in the very early development of the multiplex assays and have them as decision support tools for the pathologist in the field - not to replace them, but to provide the information in a way that the pathologist can be the ultimate decider of the result for the patient.” 

This burgeoning technology is good news for patients, Eric says. “I believe that this line of work, including the role of MMR, is going to bring true cures to more and more cancer patients, and that's tremendously exciting.”