Microsatellite instability in colorectal cancer-the stable evidence

Abstract

Microsatellite instability (MSI) is the molecular fingerprint of a deficient mismatch repair system. Approximately 15% of colorectal cancers (CRC) display MSI owing either to epigenetic silencing of MLH1 or a germline mutation in one of the mismatch repair genes MLH1, MSH2, MSH6 or PMS2. Methods to detect MSI are well established and routinely incorporated into clinical practice. A clinical and molecular profile of MSI tumors has been described, leading to the concept of an MSI phenotype in CRC. Studies have confirmed that MSI tumors have a better prognosis than microsatellite stable CRC, but MSI cancers do not necessarily have the same response to the chemotherapeutic strategies used to treat microsatellite stable tumors. Specifically, stage II MSI tumors might not benefit from 5-fluorouracil-based adjuvant chemotherapy regimens. New data suggest possible advantages of irinotecan-based regimens, but these findings require further clarification. Characterization of the molecular basis of MSI in CRC is underway and initial results show that mutations in genes encoding kinases and candidate genes with microsatellite tracts are over-represented in MSI tumors. Transcriptome expression profiles of MSI tumors and systems biology approaches are providing the opportunity to develop targeted therapeutics for MSI CRC.

Figure 2

Capillary electrophoresis of an MSI cancer. Electropherograms of the fluoresceinated amplification products for the loci BAT25 from normal colon mucosa (N) and colorectal cancer tissue (T). This loci contains (A)₂₅ repeats. Electropherograms can identify MSI CRC by the appearance of new shorter peaks owing to the shortening of the adenine repeats in cancer cells. The residual normal signal is under-represented with respect to the new unstable one, as most of the analyzed tissue is composed of neoplastic cells. Abbreviations: CRC, colorectal cancers; MSI, microsatellite instability.

Figure 3

Immunohistochemical patterns of mismatch repair proteins in colorectal cancer. Absent expression of a MLH1 and b PMS2, shown at X40 and X100 in tumor cells, with retained expression in normal colonocytes and lymphocytes. Intact expression of c MSH2 and d MSH6 shown at 40x and 100x in tumor cells and lymphocytes. Abbreviations: L, lymphocytes; T, tumor.

Figure 4

Molecular CRC groups based on a chromosomal instability and b the mutator phenotype. The genetic models for CRC tumorigenesis are also presented in parallel to each pathway for tumor development. Target therapies based on molecular events are presented for MSI tumors.