A Better Way to Identify Mismatch Repair Defects by Microsatellite Instability

Microsatellites are short, repeating DNA segments that can play a major role in studying cancers. A cellular error correction mechanism, called DNA mismatch repair, monitors genomic fidelity to keep replication mistakes in check, but the system sometimes fails. Patients with Lynch syndrome, for example, a hereditary condition in which people lose mismatch repair proteins, have a dramatically increased risk of developing colon, endometrial and other cancers. Microsatellites show changes in length, also called microsatellite instability (MSI), when mismatch repair is not working properly and can thus be used to identify these cancers.

Traditionally, pathologists have used biopsies to detect MSI, comparing microsatellite length in normal and tumor tissue using PCR and other molecular testing techniques. These diagnostic results place patients into one of three categories: MSI-high, MSI-low or microsatellite stable (MSS). This approach has been effective, but somewhat limiting, as PCR can only investigate a few microsatellites at a time.

Next-generation sequencing (NGS) has really changed the game for MSI detection. Now, pathologists can look at hundreds of microsatellites simultaneously. In addition, NGS alleviates the need to obtain normal non-tumoral tissue, as sequencing can establish a baseline for microsatellite lengths bioinformatically. Algorithms compute the likelihood an individual patient has a high MSI tumor, which may indicate they have Lynch syndrome.

Enter ctDNA

Circulating tumor DNA (ctDNA) technology offers a more comprehensive and patient-friendly way to address MSI. Combining NGS with minimally invasive blood draws, clinicians can quickly determine whether a patient has a hereditary anomaly that’s impairing mismatch repair proteins, such as Lynch syndrome, and use serial testing to guide treatment decisions.

For patients who may have MSI-high tumors, ctDNA solves a number of longstanding problems. The first is tissue scarcity. Surgical biopsies may not always produce enough tumor material to accurately assess the cancer genome. 

Another issue is patient health. In one of nature’s crueler ironies, many of the people who need testing most are least able to undergo a surgical biopsy. While the sickest patients need the most expedited and accurate genetic test results to receive the appropriate treatments, they simply cannot tolerate a surgical procedure. 

For these patients, ctDNA testing can help fill that gap. Because they require only blood samples, rather than tumor tissue, ctDNA diagnostics can provide all-important tumor mutation data, including MSI, without putting patients at further risk. 

Pathologists can readily determine if a patient has a germline mutation in a key mismatch repair protein and suffers from Lynch syndrome. This can inform the patient’s treatment plan, as well as encouraging family members to get their own genetic tests.

These diagnostics can also validate results from other tests. It is quite common for pathologists to stain tumor tissue to determine whether it contains functional mismatch repair proteins. However, these tests cannot fully assess whether these proteins are functioning properly. Though it is relatively rare for the proteins to be present and not function, it is important to get an accurate readout. Using ctDNA to assess MSI status adds a second check to ensure clinicians understand the reality inside tumors.

MSI Status and Therapeutic Choices

Equally important, ctDNA tests are ideal to monitor cancer progression (or regression) during treatment. While it would be impractical and dangerous to conduct serial surgical biopsies, blood draws are simple and pose little risk for patients.

This helps clinicians better manage the patient’s disease, as they have more consistent data about tumor status than they can get from surgical biopsies, imaging and other approaches, and this information can have a major impact on care.

Typically, patients are treated with targeted therapies. In the absence of targetable genetic alterations, immunotherapies are often introduced as the preferred line of treatment. Here’s where MSI testing can be particularly fruitful. Patients become eligible for immunotherapy when they have high tumor mutational burden (TMB), which is closely linked to MSI-high status.

In the clinical context, ctDNA diagnostics can be combined with other approaches to determine the patient’s eligibility. In addition to mismatch repair proteins, pathologists can look for a protein called PD-L1, which can indicate whether a tumor could respond favorably to immunotherapy. 

Pathologists and oncologists can triangulate on the tumor, using data from these different sources to identify the best, most personalized treatments for each patient. For this, ctDNA MSI testing has been an important milestone, providing ongoing information about each patient’s cancer that can guide treatment and even help mitigate family risk.

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