The impact of microsatellite stability status in colorectal cancer

Several forms of genomic instability are known to drive the development of colorectal cancer (CRC). Chromosomal instability is the most common type found in 85% of the CRC, while 15% patients have microsatellite instability (MSI). MSI tumors are the subset of CRC that are characterized by dysfunction of mismatch repair genes (MMR) causing failure to repair errors in repetitive DNA sequences called microsatellites. Twelve percent of MSI tumors are acquired, caused by methylation-associated silencing of a gene that encodes a DNA MMR protein, while the remaining 3% have germline mutations in one of the MMR genes (Lynch syndrome). The identification of microsatellite stability status is clinically important as studies have revealed that MSI tumors have a better stage-adjusted survival compared with microsatellite stable tumors, and they respond differently to 5FU-based adjuvant chemotherapy depending on this status. There is recent success of immunotherapy (mainly anti-PD1 drugs) in metastatic CRC with MMR dysfunction that has led to the initiation of multiple trials based on immune checkpoint inhibitors. Additionally, it is important to identify patients with Lynch syndrome so that it can guide the frequency of surveillance of CRCs and recommendations of prophylactic surgery. Even though TNM staging remains a key determinant of patient prognosis and guides management in patients with CRC, molecular tumor heterogeneity contributes to significant variability in clinical outcomes despite the same disease stage; therefore, it is vital to know the type of genomic instability pathway that the tumor harbors. In this article, we discuss the unique genetic, pathologic, and clinical characteristics of microsatellite unstable (MSI) and stable CRC (MSS), their predictive value in directing the management with conventional chemotherapy or novel-targeted agents, and their prognostic significance in patient outcomes.