Microsatellite instability in colorectal cancer

Abstract

Colorectal cancer (CRC) is a heterogeneous disease that is caused by the interaction of genetic and environmental factors. Although it is one of the most common cancers worldwide, CRC would be one of the most curable cancers if it is detected in the early stages. Molecular changes that occur in colorectal cancer may be categorized into three main groups: 1) Chromosomal Instability (CIN), 2) Microsatellite Instability (MSI), and 3) CpG Island Methylator phenotype (CIMP). Microsatellites, also known as Short Tandem Repeats (STRs) are small (1-6 base pairs) repeating stretches of DNA scattered throughout the entire genome and account for approximately 3 % of the human genome. Due to their repeated structure, microsatellites are prone to high mutation rate. Microsatellite instability (MSI) is a unique molecular alteration and hyper-mutable phenotype, which is the result of a defective DNA mismatch repair (MMR) system, and can be defined as the presence of alternate sized repetitive DNA sequences which are not present in the corresponding germ line DNA. The presence of MSI is found in sporadic colon, gastric, sporadic endometrial and the majority of other cancers. Approximately, 15-20 % of colorectal cancers display MSI. Determination of MSI status in CRC has prognostic and therapeutic implications. As well, detecting MSI is used diagnostically for tumor detection and classification. For these reasons, microsatellite instability analysis is becoming more and more important in colorectal cancer patients. The objective of this review is to provide the comprehensive summary of the update knowledge of colorectal cancer classification and diagnostic features of microsatellite instability.

Keywords: CRC; DNA MMR system; MSI.

Table 1. Types of colorectal cancer and their genes

Table 2. Microsatellite markers used to detect of MSI in CRC

Figure 1. Mechanism of mismatch repair system: (1) MutSα or MutSβ has recognized the mismatched DNA base pairs during replication that the DNA polymerase has matched the mistake base G (guanosine) in daughter strand with the T (thymidine) on the template. MutSα or MutSβ can recruit MutLα, MutLβ or MutLγ heterodimers by means of exchanging ATP to ADP. This complex (MutS-MutL) creates a sliding clamp around the DNA and moves along the new DNA chain when it encounters the DNA polymerase complex. (2) The proteins in sliding clamp interact with exonuclease-1 (EXO1) and proliferating cell nuclear antigen (PCNA). This complex excises the daughter strand back to the site of the mismatch. Finally, re-synthesize and re-ligation are performed by DNA polymerase and DNA ligase, respectively. The correction occurs (Boland and Goel, 2010).