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A Performance Characterization of Microsatellite Instability and Mismatch Repair Testing Methods in Endometrial Samples

Lewis, S. R. et al., Promega Corporation


AACR 2020 Abstract #4251

Microsatellite instability (MSI), a functional measure of mismatch repair (MMR) deficiency, and immunohistochemistry testing for MMR proteins are well established technologies traditionally used for Lynch Syndrome screening in colorectal cancer. Recently testing for MMR deficiency, by MSI analysis or MMR protein expression, has expanded from hereditary cancer risk testing to a new role predicting immunotherapeutic response in all solid tumors. With this increase in utility and awareness, mismatch repair deficiency is now relevant in a variety of other cancer tissue types. However, little data is available for the performance of these testing techniques in non-colorectal cancer samples.

In this study, we examine performance of methods for detecting MSI and MMR protein expression in endometrial cancer samples. 200 endometrial cancer samples were obtained for testing with MSI by PCR followed by capillary electrophoresis, and immunohistochemistry for MMR protein expression. Instability at 2/5 microsatellite loci was used as criteria for MSI-H designation and loss of immunostaining for one or more MMR protein was considered dMMR. Performance of these analysis methods for identification of MMR protein mutations was measured by comparing results to sequencing of MMR proteins using NGS. MSI by PCR followed by capillary electrophoresis and immunohistochemistry for all four major MMR proteins was successfully performed on all (200/200) samples. 140/200 samples had matched adjacent tissue for reference when performing MSI analysis. MSI and MMR did not exhibit 100% concordance, as expected due to their measurement of different biological effects associated with MMR deficiency. We also describe instances of microsatellite loci exhibiting more subtle shifts than those commonly observed in colorectal cancer, especially at shorter nucleotide repeats, an important consideration for future studies with pan-tumor MSI testing. With the increasing utility of identifying mismatch repair defects in hereditary and immuno-oncology for pan-tumor applications, choosing a testing approach that has the highest sensitivity is key.

Our findings suggest that for maximal identification of mismatch repair deficiency, MMR by IHC and MSI by PCR are complementary technologies and should not be considered interchangeable. Consistent with these findings, a number of guideline committees globally have begun recommending co-testing for MMR and MSI. These two cost effective tools can be used together for both a functional and informative approach prior to more costly downstream testing.

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