Heterogeneity of mismatch repair protein expression in tumors

The genes of mismatch repair system (MMR) are responsible for correcting errors in DNA replication. MMR defects (dMMR) lead to mutations in microsatellites - repetitive nucleotide base sequences - resulting in microsatellite instability (MSI). Determination of dMMR/MSI status in tumors is an important factor for the development of patient management tactics, as the dMMR/MSI phenotype serves as both a marker of favorable prognosis and a predictor of response to immunotherapy in tumors of many localizations. MMR status is assessed via immunohistochemistry (IHC) on histological material. However, in some cases heterogeneity of intratumoral MMR protein expression (MMR heterogeneity) becomes an obstacle to this. MMR heterogeneity (areas of weak/absent staining on the background of normal expression) is poorly studied, especially in gastric cancer, in contrast to colorectal cancer and endometrial cancer. The lack of a methodology for interpreting this phenomenon leads to significant difficulties in stratifying patients who are indicated for dMMR/MSI status determination. The article systematizes current data on MMR heterogeneity in gastric cancer and tumors of other localizations, discusses molecular mechanisms, clinical significance and recommendations to overcome diagnostic limitations.