Microsatellite instability and DNA mismatch repair deficiency testing in hereditary and sporadic gastrointestinal cancers

The reference cancers associated with DNA mismatch repair (MMR) deficiency are the adenocarcinomas of patients with hereditary nonpolyposis colorectal cancer, also known is Lynch syndrome, Sporadic gastrointestinal (GI) carcinomas, most commonly colorectal and gastric carcinomas, may also be associated with deficiencies of DNA mismatch repair. Deficiency in cellular MMR leads to widespread mutagenesis and neoplastic development and progression. An important diagnostic feature of MMR-deficient tumors is the high rate of mutations that accumulate in repetitive nucleotide regions, and these Mutations are known as microsatellite instability (MSI). A standard panel of markers to test for MSI in tumors has. been recommended and efficiently separates tumors into those with high, low, or no microsatellite instability (MSH-II, MSI-L, or MSS). Tumors characterized by MSI-II characteristically show loss of one of the main DNA MMR proteins, mLIII or MSII2, and rarely MSH6 and PMS2, detected by immunohistochemistry (IHC). The combination of MSI testing and IHC for MMR proteins in tumors tissues is used to identify underlying DNA MMR deficiency and is clinically relevant screen patients who might have hereditary nonpolyposis colorectal cancer for DNA repair gene germline testing. Increasing evidence demonstrates that tumors with a positive MSI status have lower lymph node metastases burden, and these patients have an overall improved Survival, Suggesting that the MSI and MMR status may contribute to decision making regarding treatment approaches. Updated guidelines for MSI and IHC for DNA MMR testing, and the biological and potential clinical implications of MMR deficiency and microsatellite instability in GI polyps and cancers are reviewed.