Iacopetta Barry, Grieu Fabienne, Amanuel Benhur
School of Surgery, University of Western Australia Anatomical Pathology, Pathwest, Nedlands, Western Australia, Australia.
Asia Pac J Clin Oncol. 2010 Dec;6(4):260-9. doi: 10.1111/j.1743-7563.2010.01335.x. Epub 2010 Oct 26.
Approximately 20 percent of right-sided colon cancers and 5 percent of left-sided colon and rectal cancers have a deficient DNA mismatch repair system. This results in the widespread accumulation of mutations to nucleotide repeats, some of which occur within the coding regions of cancer-related genes such as TGFβRII and BAX. A standardized definition for microsatellite instability (MSI) based on the presence of deletions to mononucleotide repeats is gaining widespread acceptance in both research and the clinic. Colorectal cancer (CRC) with MSI are characterized histologically by an abundance of tumor-infiltrating lymphocytes, poor differentiation and a signet ring or mucinous phenotype. In younger patients these tumors usually develop along the chromosomal instability pathway, in which case the mismatch repair genes are inactivated by germline mutation, somatic mutation and loss of heterozygosity. In older patients MSI CRC usually develops against a background of widespread hypermethylation that includes methylation-induced silencing of the mismatch repair gene MLH1. The overall biological and clinical phenotype of MSI CRC that arise in these two pathways is likely to be different and may account for some of the discordant results reported in the literature relating to the clinical properties of these tumors. The available evidence indicates that MSI is unlikely to be a clinically useful marker for the prognostic stratification of early-stage CRC. The predictive value of MSI for response to 5-fluorouracil-based chemotherapy remains controversial, while for other agents the predictive value is difficult to assess because they are used in combination regimens. The MSI phenotype is being actively investigated for novel therapeutic approaches based on the principle of synthetic lethality. Finally, the MSI status of CRC is an extremely useful marker for population-based screening programs that aim to identify individuals and families with the hereditary cancer condition known as Lynch syndrome.
约20%的右半结肠癌以及5%的左半结肠癌和直肠癌存在DNA错配修复系统缺陷。这导致核苷酸重复序列的突变广泛积累，其中一些发生在癌症相关基因（如TGFβRII和BAX）的编码区域内。基于单核苷酸重复序列缺失的微卫星不稳定性（MSI）的标准化定义在研究和临床中都得到了广泛认可。MSI的结直肠癌在组织学上的特征是大量肿瘤浸润淋巴细胞、低分化以及印戒或黏液样表型。在年轻患者中，这些肿瘤通常沿着染色体不稳定途径发展，在这种情况下，错配修复基因通过种系突变、体细胞突变和杂合性缺失而失活。在老年患者中，MSI结直肠癌通常在广泛的高甲基化背景下发生，包括甲基化诱导错配修复基因MLH1的沉默。在这两种途径中发生的MSI结直肠癌的总体生物学和临床表型可能不同，这可能解释了文献中报道的关于这些肿瘤临床特性的一些不一致结果。现有证据表明，MSI不太可能成为早期结直肠癌预后分层的临床有用标志物。MSI对基于5-氟尿嘧啶化疗反应的预测价值仍存在争议，而对于其他药物，由于它们用于联合治疗方案，其预测价值难以评估。基于合成致死原理，正在积极研究MSI表型的新型治疗方法。最后，结直肠癌的MSI状态是基于人群的筛查项目中一个极其有用的标志物，这些项目旨在识别患有遗传性癌症综合征（即林奇综合征）的个体和家庭。
