INSERM, UMR_S, Centre de Recherche Saint-Antoine, Paris, France.
Cell Oncol (Dordr). 2011 Jun;34(3):155-76. doi: 10.1007/s13402-011-0024-x. Epub 2011 Apr 12.
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.
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.
In view of this, the opportunity of a systematic MSI phenotyping in the clinical management of patients with CRC is further discussed.
微卫星不稳定性（MSI）构成了结直肠癌（CRC）中重要的致癌分子途径，约占所有结直肠恶性肿瘤的 15%。在大约三分之一的病例中，潜在的 DNA 错配修复（MMR）缺陷是通过参与 MMR 的基因之一的突变遗传的，主要是 MSH2 和 MLH1，或者不太常见的是 MSH6 或 PMS2。在绝大多数散发性病例中，MSI 是由于 MLH1 启动子的超甲基化导致其表观遗传沉默所致。MMR 缺陷通过在含有单核苷酸重复的关键靶基因中积累大量突变促进结直肠肿瘤发生，这些突变基因参与细胞增殖和分化的调控，以及 DNA 损伤信号转导和修复。
在这篇综述中，我们描述了 MMR 系统的分子方面及其缺陷对致癌过程的生物学后果，并讨论了用于评估细胞毒性药物对 MSI 结直肠细胞系疗效的各种实验系统。越来越多的证据表明，MSI CRC 在预后和对各种化疗方案的治疗反应方面与所有 CRC 不同。我们报告了评估 MSI 状态对接受辅助治疗或晚期 CRC 治疗的患者临床结局的预后和预测价值的临床研究。
有鉴于此，进一步讨论了在 CRC 患者的临床管理中进行系统 MSI 表型分析的机会。
