Contribution of microsatellite instability (MSI) in Colorectal Cancer

Avishek Roy

Scientific Liaison Manager
4baseCare

Colorectal cancer (CRC) is a heterogeneous disease caused by the interaction of hereditary and environmental factors. CRC, although being one of the most common cancers globally, is one of the most treatable tumors if detected early. Colorectal cancer-related molecular alterations that silences gene function with aberrant hypermethylation can be divided into three categories: 1) Chromosomal Instability (CIN), 2) Microsatellite Instability (MSI), and 3) CpG Island Methylator phenotype (CIMP).

Mismatch repair (MMR) genes (MLH1, MLH3, PMS2, MSH2, MSH3, and MSH6) identify and repair mismatched nucleotides in DNA, especially in microsatellite regions. Hereditary non-polyposis colon cancer (HNPCC), the most common form of hereditary colon cancer, is a syndrome of deficient DNA mismatch repair (dMMR). Microsatellites, also known as Short Tandem Repeats (STRs), are short (1-6 base pair) repeating segments of DNA found throughout the human genome (both coding and non-coding sections) and makeup around 3% of the genome. Microsatellites are prone to high mutation rates due to their repetitive structure during the DNA replication process.

Microsatellite instability is the presence of alternative-sized repeating DNA sequences in tumor DNA that are not present in the matching germline DNA. Microsatellite instability is caused by mismatch repair deficiency (MMR-D or dMMR) caused by germline (Lynch syndrome) or somatic changes in either of the MMR genes, which results in an increase or reduction in the size of microsatellites. Because of the instability of microsatellites, DNA mutations accumulate, resulting in carcinogenesis due to oncogene activation and perhaps loss of function in tumor suppressor genes. In around 15% of colorectal tumors, MSI is present. The genetic or epigenetic alterations of the DNA mismatch repair genes may have prognostic value in some CRC patients. According to a recent study, MSI happens to be a good predictor of immunotherapy response in CRC. After a diagnosis of CRC, most individuals should be tested for MSI, both for hereditary syndrome screening and for prognostic and therapeutic implications.

Immunohistochemistry (IHC) and polymerase chain reaction (PCR)-based approaches are presently used to identify microsatellite instability. IHC examines tumor samples for MLH1, MSH2, MSH6, and PMS2 staining to determine the reduction of protein expression that characterizes MMR-D as a surrogate for MSI. A PCR-based technique to molecular DNA testing assesses a specific panel of microsatellite markers to detect loci with instability. MSI-high (MSI-H) tumors have 30 percent or more of their loci unstable, while MSI-low (MSI-L) tumors have less than 30 percent of their loci unstable. If MSI (PCR-based approach) or MMR-D (IHC-based method) is found, additional testing to identify carriers of germline MMR gene mutations is indicated.

Microsatellite instability is an important genetic marker in CRC that can help with diagnosis, prognosis, and chemotherapeutic treatment effectiveness prediction. In CRC, the presence of MSI indicates a favorable result. The survival rate of CRC patients with MSI tumors has been found to be up to 15% greater than that of CRC patients with microsatellite stable (MSS) tumors. A meta-analysis of 7642 CRC patients, including 1277 MSI-H patients, showed that MSI-H tumors were associated with a better prognosis than microsatellite stable (MSS) tumors (hazard ratio for overall survival 0.65). In addition, the treatment options for stage II CRC are highly influenced by MSI status. The National Comprehensive Cancer Network (NCCN) guideline does not recommend chemotherapy for these patients because of the good prognosis of MSI high patients with stage II CRC.

With the success of precision oncology medicine, researchers have focused their efforts on developing novel biomarkers for use in CRC clinical diagnosis, prediction, and prognosis. Molecular approaches for detecting MSI have been discovered recently, and drug development strategies are now focusing on specific tumor molecular characteristics. The three types of chemotherapeutic medicines utilized in CRC therapy include anti-metabolites (5-fluorouracil), alkylating agents, and topoisomerase inhibitors. Although chemotherapeutic therapy is helpful in some patients, it can also have a number of side effects. Because microsatellite-instability–high (MSI-H) is one of the possible predictors of chemotherapeutic treatment success and the number of side effects in a patient, various clinical trials have been carried out in this field. After prior therapy, programmed death 1 (PD-1) blocking, for example, offers therapeutic benefits in MSI-H cancers. When used as first-line therapy for MSI-H–metastatic colorectal cancer, the PD-1 inhibitor Pembrolizumab led to significantly longer progression-free survival than chemotherapy, with fewer treatment-related side events, according to research. As a result, pembrolizumab was rapidly approved by the US Food and Drug Administration for the treatment of metastatic/refractory MSI-H CRC.