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Microsatellite instability in colorectal cancer—the stable evidence

Nature Reviews Clinical Oncology volume 7, pages 153–162 (2010)Cite this article

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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.

Key Points

  • Microsatellite instability (MSI) is present in approximately 15% of colorectal cancers (CRC), which are mostly nonfamilial (sporadic) and caused by hypermethylation of the MLH1 promoter

  • Approximately 2–3% of all CRC are caused by germline mutations in one of the mismatch repair genes (MLH1, MSH2, MSH6 and PMS2)

  • The MSI phenotype is characterized by right-sided location, low pathological stage, mucinous presentation, tumor-infiltrating lymphocytes, absence of necrotic cellular debris and the presence of a Crohn-like nodular infiltrate

  • MSI tumors have a good prognosis and reduced likelihood of metastasis compared with microsatellite stable tumors, which highlights the value of MSI as a prognostic marker in CRC

  • Although 5-fluorouracil-based chemotherapy is the gold standard for CRC, this drug offers little benefit in early MSI CRC—irinotecan-based regimens and other drugs may hold promise, and are being studied in MSI CRC

  • Transcriptome expression studies that characterize MSI tumors and cell lines have identified unique attributes of MSI cancers, and systems biology tools and other approaches enable investigation of targeted therapies

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Figure 1: Model of the proposed mechanism of mismatch repair proteins, illustrating patterns of clinically relevant heterodimerization.
Figure 2: Capillary electrophoresis of an MSI cancer.
Figure 3: Immunohistochemical patterns of mismatch repair proteins in colorectal cancers.
Figure 4: CRC progression models and therapeutic targets in MSI and MSS CRC.

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Acknowledgements

E. Vilar was supported by a fellowship from “la Caixa”, Barcelona, Spain. S. B. Gruber's laboratory work is supported by NCI grant 1R01CA81488 and by the University of Michigan Comprehensive Cancer Center Core Support grant NIH 5P30CA46592.

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  1. Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, University of Michigan Medical School, 1524 BSRB, 109 Zina Pitcher, Ann Arbor, 48109, MI, USA

    Eduardo Vilar & Stephen B. Gruber

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Vilar, E., Gruber, S. Microsatellite instability in colorectal cancer—the stable evidence. Nat Rev Clin Oncol 7, 153–162 (2010). https://doi.org/10.1038/nrclinonc.2009.237

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