Cellular Oncology

, Volume 34, Issue 3, pp 155–176 | Cite as

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

  • Aziz Zaanan
  • Katy Meunier
  • Fatiha Sangar
  • Jean-François Fléjou
  • Françoise Praz
Review

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 

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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Copyright information

© International Society for Cellular Oncology 2011

Authors and Affiliations

  • Aziz Zaanan
    • 1
    • 2
    • 3
  • Katy Meunier
    • 1
    • 2
    • 4
  • Fatiha Sangar
    • 1
    • 2
  • Jean-François Fléjou
    • 1
    • 2
    • 5
  • Françoise Praz
    • 1
    • 2
    • 6
  1. 1.INSERM, UMR_S 938Centre de Recherche Saint-AntoineParisFrance
  2. 2.UPMC Univ Paris 06, UMR_S 938Centre de Recherche Saint-AntoineParisFrance
  3. 3.Service d’Oncologie Médicale, Hôpital Saint-AntoineAssistance Publique - Hôpitaux de ParisParisFrance
  4. 4.Service de Chirurgie OncologiqueCentre Paul PapinAngersFrance
  5. 5.Service d’Anatomie et Cytologie Pathologique, Hôpital Saint-AntoineAssistance Publique - Hôpitaux de ParisParisFrance
  6. 6.Centre de Recherche Saint-Antoine, INSERM UMRS_938-UPMCParisFrance

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