title: Microsatellite instability in colorectal cancer: from molecular oncogenic mechanisms to clinical implications.
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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  In view of this, the opportunity of a systematic MSI phenotyping in the clinical management of patients with CRC is further discussed.
authors.affiliation: INSERM, UMR_S, Centre de Recherche Saint-Antoine, Paris, France.
authors.forename: Aziz
authors.initials: A
authors.lastname: Zaanan
authors.forename: Katy
authors.initials: K
authors.lastname: Meunier
authors.forename: Fatiha
authors.initials: F
authors.lastname: Sangar
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Fléjou
authors.forename: Françoise
authors.initials: F
authors.lastname: Praz
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity; D016923:Cell Death / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D053843:DNA Mismatch Repair / Q000187:drug effects / Q000235:genetics; D006801:Humans; D053842:Microsatellite Instability; D010641:Phenotype
chemical_list: D000970:Antineoplastic Agents