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Microsatellite instability in colorectal cancer: from molecular oncogenic mechanisms to clinical implications

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An Erratum to this article was published on 31 May 2011

Abstract

Background

Microsatellite instability (MSI) constitutes an important oncogenic molecular pathway in colorectal cancer (CRC), representing approximately 15% of all colorectal malignant tumours. In roughly one third of the cases, the underlying DNA mismatch repair (MMR) defect is inherited through the transmission of a mutation in one of the genes involved in MMR, predominantly MSH2 and MLH1, or less frequently, MSH6 or PMS2. In the overwhelming number of sporadic cases, MSI results from epigenetic MLH1 silencing through hypermethylation of its promoter. MMR deficiency promotes colorectal oncogenesis through the accumulation of numerous mutations in crucial target genes harbouring mononucleotide repeats, notably in those involved in the control of cell proliferation and differentiation, as well as DNA damage signalling and repair.

Design

In this review, we describe the molecular aspects of the MMR system and the biological consequences of its defect on the oncogenic process, and we discuss the various experimental systems used to evaluate the efficacy of cytotoxic drugs on MSI colorectal cells lines. There is increasing evidence showing that MSI CRCs differ from all CRCs in terms of prognosis and response to the treatment. We report the clinical studies that have evaluated the prognostic and predictive value of MSI status on clinical outcome in patients treated with various chemotherapy regimens used in the adjuvant setting or for advanced CRCs.

Conclusion

In view of this, the opportunity of a systematic MSI phenotyping in the clinical management of patients with CRC is further discussed.

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Abbreviations

5FU:

5-fluorouracil

ACVR2:

Activin type II receptor

CAPOX:

Capecitabine and oxaliplatin

CIMP:

CpG island methylator phenotype

CRC:

Colorectal cancer

DFS:

Disease-free survival

EGFR:

Epidermal growth factor receptor

FOLFOX:

5-fluorouracil and oxaliplatin

HNPCC:

Hereditary non-polyposis colorectal cancer

HR:

Hazard ratio

IDL:

Insertion-deletion loop

IHC:

Immunohistochemistry

mCRC:

Metastatic colorectal cancer

MSI:

Microsatellite instability

MMR:

Mismatch repair

MSS:

Microsatellite stable

NER:

Nucleotide excision repair

OR:

Odds ratio

OS:

Overall survival

PFS:

Progression-free survival

RFS:

Relapse-free survival

RR:

Response rate

TGFBR2:

Transforming growth factor β receptor 2

TIL:

Tumour-infiltrating lymphocytes

VEGF:

Vascular endothelial growth factor

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Authors and Affiliations

  1. INSERM, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012, Paris, France

    Aziz Zaanan, Katy Meunier, Fatiha Sangar, Jean-François Fléjou & Françoise Praz

  2. UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012, Paris, France

    Aziz Zaanan, Katy Meunier, Fatiha Sangar, Jean-François Fléjou & Françoise Praz

  3. Service d’Oncologie Médicale, Hôpital Saint-Antoine, Assistance Publique - Hôpitaux de Paris, 75012, Paris, France

    Aziz Zaanan

  4. Service de Chirurgie Oncologique, Centre Paul Papin, Angers, France

    Katy Meunier

  5. Service d’Anatomie et Cytologie Pathologique, Hôpital Saint-Antoine, Assistance Publique - Hôpitaux de Paris, 75012, Paris, France

    Jean-François Fléjou

  6. Centre de Recherche Saint-Antoine, INSERM UMRS_938-UPMC, 184 rue du Faubourg Saint-Antoine, 75571, Paris, Cedex 12, France

    Françoise Praz

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An erratum to this article can be found at http://dx.doi.org/10.1007/s13402-011-0050-8

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Zaanan, A., Meunier, K., Sangar, F. et al. Microsatellite instability in colorectal cancer: from molecular oncogenic mechanisms to clinical implications. Cell Oncol. 34, 155–176 (2011). https://doi.org/10.1007/s13402-011-0024-x

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