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  • Review Article
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Mismatch repair deficient colorectal cancer in the era of personalized treatment

Nature Reviews Clinical Oncology volume 7, pages 197–208 (2010)Cite this article

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Abstract

The molecular and genetic subtyping of cancer has allowed the emergence of individualized therapies. This approach could potentially deliver treatments that have both increased efficacy as well as reduced toxicity. A well-defined subtype of colorectal cancer (CRC) is characterized by a deficiency in the mismatch repair (MMR) pathway. MMR deficiency not only contributes to the pathogenesis of a large proportion of CRC, but also determines the response to many of the drugs that are frequently used to treat this disease. In this Review we describe the MMR deficient phenotype and discuss how a deficiency in this DNA repair process may impact on the management of CRC, including surgery, adjuvant chemotherapy and the choice of systemic agents for the palliation of advanced disease. We also discuss how the DNA repair defect in MMR deficient CRC could be exploited in the development of novel therapeutic strategies.

Key Points

  • Deficient MMR (dMMR) in colorectal cancer (CRC) occurs as a result of inherited or sporadic abnormalities

  • Phenotypic characteristics, such as proximal anatomical location, mucinous features, lymphocytic infiltration, and pushing margins help to identify dMMR tumors

  • The presence of dMMR in a tumor may be of relevance to the surgical management and systemic treatment of a patient

  • Preclinical investigations suggest that cancer cells with dMMR show resistance to 5-fluorouracil, but are sensitive to irinotecan and mitomycin C; clinical data corroborate these findings although further studies are required

  • Heterogeneity exists within the dMMR CRC subtype, which could be explained by the presence or absence of secondary mutations that occur as a consequence of the dMMR-associated mutator phenotype

  • dMMR and the mutations that arise as a result of this deficiency could be exploited as novel therapeutic targets

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Figure 1: Schematic representation of mismatches and the MMR pathway.
Figure 2: Genes mutated in dMMR cells and tumors.
Figure 3: The impact of dMMR on the management of colorectal cancer.
Figure 4: The futile cycling and direct damage signaling models.2,119
Figure 5: Novel strategies for the treatment of dMMR tumors.

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Acknowledgements

The authors acknowledge NHS funding to the NIHR Biomedical Research Centre.

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Authors and Affiliations

  1. Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, Fulham Road, London, SW3 6JB, UK

    Madeleine Hewish, Christopher J. Lord, Sarah A. Martin & Alan Ashworth

  2. The Royal Marsden Hospital NHS Trust, Downs Road, Sutton, SM2 5PT, Surrey, UK

    David Cunningham

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  1. Madeleine Hewish
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Correspondence to Alan Ashworth.

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Competing interests

A. Ashworth and C. J. Lord report that they may benefit financially from the development of PARP inhibitors through patents held with Kudos-Astra Zeneca, and through the Institute of Cancer Research 'Rewards to Inventors' scheme.

A. Ashworth, C. J. Lord and S. A. Martin have a patent pending on the use of methotrexate in mismatch repair-deficient cancers.

D. Cunningham has received a grant from The Royal Marsden NHS Foundation and has also worked as a consultant for this Trust.

M. Hewish declares no competing interests.

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Hewish, M., Lord, C., Martin, S. et al. Mismatch repair deficient colorectal cancer in the era of personalized treatment. Nat Rev Clin Oncol 7, 197–208 (2010). https://doi.org/10.1038/nrclinonc.2010.18

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