Molecular pathways: microsatellite instability in colorectal cancer: prognostic, predictive, and therapeutic implications

Abstract

Microsatellite instability (MSI) is the molecular fingerprint of the deficient mismatch repair (MMR) system, which characterizes ∼15% of colorectal cancers. MSI develops as a result of germline mutations in MMR genes or, more commonly, from epigenetic silencing of MLH1 in sporadic tumors occurring in a background of methylation of CpG islands in gene promoter regions and in tumors that frequently show hotspot mutations in the BRAF oncogene. MSI tumors have distinct phenotypic features and have been consistently associated with a better stage-adjusted prognosis compared with microsatellite stable tumors. MSI negatively predicts response to 5-fluorouracil and may also determine responsiveness to other drugs used for treatment of colorectal cancers. Recent data have expanded the molecular heterogeneity of MSI tumors and may contribute to our understanding of differential chemosensitivity. The ability to identify deficient MMR has important implications for patient management, and it holds promise for therapeutic exploitation and for the development of novel therapeutics.

Fig. 1

The MMR system functions to correct errors introduced in microsatellites through a series of steps involving the interaction of MMR proteins as heterodimers (A) MSH2 –MSH6 (MutSα) recognizes single base-pair mismatches, shown by the incorrect base (G) matched with T on the template, and creates a sliding clamp around the DNA. This step requires the exchange of adenosine triphoshpate (ATP) for adenosine diphosphate (ADP). The MutSα complex is then bound by the MLH1-PMS2 (MutLα) complex. (B) Excision of the mismatch occurs when the DNA MMR protein sliding clamp interacts with exonuclease-1, proliferating cell nuclear antigen (PCNA), and DNA polymerase. This complex excises the daughter strand back to the site of the mismatch. The complex comes off the DNA and resynthesis then occurs with correction of the error. (C) MSH2 – MSH3 (MutSβ) can recognize larger insertion deletion loops (IDLs) that can complement the function of MSH2 – MSH6 that recognizes single pair mismatches and small IDLs. Potential interactions with other MutL dimers are shown, as. MLH1 can dimerize with PMS2, PMS1, or MLH3. (Reprinted with permission from Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology. 2010;138:2073–87.)

Fig. 2

Two molecular pathways can lead to CRCs with MSI. These include germline mutations in a MMR gene followed by a second hit to the wild-type copy that may occur due to point mutation, LOH or methylation. Germline MMR mutations lead to Lynch Syndrome (LS) that represents approximately one-fifth of all MSI CRCs. The more common, non familial form of MSI is due to epigenetic inactivation of MLH1 that occurs in a background of CIMP that results in hypermethylation of the promoters of multiple genes. These sporadic tumors show CIMP and BRAFV600E hotspot mutations that serve to distinguish them from LS cases.