Review

Cellular Oncology

, Volume 34, Issue 3, pp 155-176

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

  • Aziz ZaananAffiliated withINSERM, UMR_S 938, Centre de Recherche Saint-AntoineUPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-AntoineService d’Oncologie Médicale, Hôpital Saint-Antoine, Assistance Publique - Hôpitaux de Paris
  • , Katy MeunierAffiliated withINSERM, UMR_S 938, Centre de Recherche Saint-AntoineUPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-AntoineService de Chirurgie Oncologique, Centre Paul Papin
  • , Fatiha SangarAffiliated withINSERM, UMR_S 938, Centre de Recherche Saint-AntoineUPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine
  • , Jean-François FléjouAffiliated withINSERM, UMR_S 938, Centre de Recherche Saint-AntoineUPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-AntoineService d’Anatomie et Cytologie Pathologique, Hôpital Saint-Antoine, Assistance Publique - Hôpitaux de Paris
  • , Françoise PrazAffiliated withINSERM, UMR_S 938, Centre de Recherche Saint-AntoineUPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-AntoineCentre de Recherche Saint-Antoine, INSERM UMRS_938-UPMC Email author 

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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.

Keywords

Biomarker Chemotherapy Colorectal cancer Microsatellite instability Mismatch repair Prognosis