MSI for Lynch Syndrome Screening and Guiding Immunotherapy

As described in a previous article, microsatellite instability (MSI) is a hallmark of certain types of cancer. The presence and level of MSI in a tumor sample can offer insight into tumor pathology and inform treatment options, making the evaluation of tumor samples for MSI an important part of understanding the cause and management of many types of cancer. As Dr. Paul Walker, Chief Medical Officer at Circulogene, explains in this video, MSI testing is critically important for solid-tumor patients in particular, for whom the outcome of this test can mean the difference between ineffective and effective standard treatments.

MSI testing enables two key applications: looking for MSI associated with Lynch syndrome and identifying the right patients to target with checkpoint inhibition immunotherapies.

MSI as a predictor for Lynch syndrome

Lynch syndrome, also known as hereditary non-polyposis colorectal cancer (HNPCC), arises from germline defects in the mismatch repair (MMR) pathway, often abbreviated as dMMR. It is primarily associated with colorectal cancer, as the name suggests, but it is also connected to various other cancer types. Endometrial, small bowel, gastric, ovarian, melanoma and prostate cancer are all among the cancer types to which Lynch syndrome is linked, and evidence continues to accumulate that the set of Lynch syndrome–related cancers is much larger than previously known. The defects in MMR that characterize Lynch syndrome have particularly large effects on microsatellite regions, making MSI screening an ideal tool for identifying and studying Lynch syndrome–related cancers. MSI-high (typically measured as 30% or more of a set of microsatellite loci showing instability) is predictive of Lynch syndrome across tumor types. After a long history of being used to classify colorectal cancers, MSI testing is increasingly recognized as important for classifying other cancer types. The National Comprehensive Cancer Network™ (NCCN) guidelines provide recommendations for investigating MSI with PCR and MMR with immunohistochemistry (IHC) for 15 different cancer types.

Using MSI to select patients for immunotherapy

Defects in the MMR pathway result in a buildup of somatic mutations throughout the genome. Although many of these have no functional effect, others can produce novel immunogenic proteins that “prime” an immune response to the foreign neoantigens on the tumor. MSI-high tumors, whose level of MSI indicates a high level of somatic mutation in general, are thus more sensitive to immune checkpoint inhibitor treatments than microsatellite-stable (MSS) tumors. In 2018, the FDA granted accelerated approval to pembrolizumab for pediatric and adult patients with MSI-H (or dMMR) solid tumors of all types. This is the first time a cancer treatment has been approved based on a common (tumor-agnostic) biomarker.¹ More such interventions are sure to follow.

Conclusion

MSI is an under-studied diagnostic tool in cancer biology. This biomarker provides insight into diverse tumor types and can inform treatment options, making the difference between long periods of trial and error and swift deployment of more effective medications. Given that many cancer treatments come with difficult and harmful side effects, choosing the right treatment is vitally important and any tool that makes that easier is worth exploring. Thus there is substantial interest in analyzing MSI in diverse tumor types to identify those whose growth might be slowed by immune checkpoint inhibitor treatments and to find out if a patient is at risk of having Lynch syndrome and consequently more prone to developing certain cancers. MSI testing is, therefore, a central part of the future of personalized medicine, both for Lynch syndrome screening and for solid tumor treatment at large.

Reference:

1. Chang, L., et al. (2018). “Microsatellite instability: A predictive biomarker for cancer immunotherapy.” Appl Immunohistochem Mol Morphol26(2):e15–e21.