Carethers John M
Division of Gastroenterology, Department of Internal Medicine and Department of Human Genetics and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109-5368.
Curr Colorectal Cancer Rep. 2017 Feb;13(1):73-80. doi: 10.1007/s11888-017-0352-y. Epub 2017 Feb 2.
Microsatellite instability (MSI) refers to the biochemical detection of frameshifted microsatellite sequences from genomic DNA. Genesis of MSI is due to defective DNA mismatch repair (MMR) that fails to correct post DNA replicative slippage mistakes at microsatellites. Most of the estimated 100,000 genomic microsatellites are non-coding; however, ~150-300 microsatellites are coding such that, when frameshifted during the pathogenesis of an MSI tumor, can generate immunogenic neopeptide antigens that limit the growth of tumor and prolong patient survival. In addition to the immune reaction and longer survival, patients with MSI colorectal cancers tend to have poorly differentiated tumors with mucinous features that are located in the right colon. Patients with MSI tumors are more resistant to 5-fluorouracil-based adjuvant chemotherapy but may be responsive to PD-1 immune checkpoint blockade. Specific defects of MMR function not only drive MSI but also elevate microsatellite alterations at selected tetranucleotide repeats that may further modify patient outcome.
微卫星不稳定性（MSI）是指从基因组DNA中对移码微卫星序列进行的生化检测。MSI的发生是由于DNA错配修复（MMR）缺陷，无法纠正微卫星处DNA复制后滑链错误。估计10万个基因组微卫星中的大多数是非编码的；然而，约150 - 300个微卫星是编码的，因此，在MSI肿瘤发病过程中发生移码时，可产生免疫原性新肽抗原，限制肿瘤生长并延长患者生存期。除了免疫反应和更长的生存期外，MSI结直肠癌患者的肿瘤往往分化差，具有黏液特征，且位于右半结肠。MSI肿瘤患者对基于5-氟尿嘧啶的辅助化疗更具抗性，但可能对PD-1免疫检查点阻断有反应。MMR功能的特定缺陷不仅驱动MSI，还会增加选定四核苷酸重复序列处的微卫星改变，这可能进一步改变患者的预后。
