Inflammation-associated microsatellite alterations: Mechanisms and significance in the prognosis of patients with colorectal cancer.
Inflammation-associated microsatellite alterations: Mechanisms and significance in the prognosis of patients with colorectal cancer.
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DOI：
10.4251/wjgo.v10.i1.1
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发表时间：
2018-01-15
影响因子：
3
通讯作者：
Carethers JM
中科院分区：
文献类型：
--
作者：
Koi M;Tseng-Rogenski SS;Carethers JM
DNA错配修复缺陷（MMR）导致基因组DNA移码内的微卫星改变。大约15%的散发性结直肠癌（crc）表现出DNA MMR基因MLH1的高甲基化，导致单核苷酸和双核苷酸帧移，将其归类为微卫星不稳定性高（MSI-H）和超突变，并且由于编码微卫星的帧移产生新抗原，产生强大的保护性免疫反应，可以通过免疫检查点阻断来增强。更常见的是，大约50%的散发性非msi - h crc在二核苷酸和四核苷酸微卫星上表现出帧移，将其分类为选择性四核苷酸重复（EMAST）上的msi -低/升高微卫星改变，这是DNA MMR蛋白MSH3通过核到胞质位移的功能性体细胞失活的结果。MSH3移位的触发因素似乎是炎症和/或氧化应激，与MSI-H型CRC患者不同，MSI-L/EMAST型CRC患者预后较差。这些炎症相关的微卫星改变是局部肿瘤微环境的结果，理论上，如果微环境被操纵以降低炎症，微卫星改变和MSH3功能障碍应该得到纠正。在这里，我们描述了炎症相关微卫星改变的机制和意义，并提出了三个领域来深入探索炎症对DNA MMR系统影响的后果和预防。
Microsatellite alterations within genomic DNA frameshift as a result of defective DNA mismatch repair (MMR). About 15% of sporadic colorectal cancers (CRCs) manifest hypermethylation of the DNA MMR gene MLH1, resulting in mono- and di-nucleotide frameshifts to classify it as microsatellite instability-high (MSI-H) and hypermutated, and due to frameshifts at coding microsatellites generating neo-antigens, produce a robust protective immune response that can be enhanced with immune checkpoint blockade. More commonly, approximately 50% of sporadic non-MSI-H CRCs demonstrate frameshifts at di- and tetra-nucleotide microsatellites to classify it as MSI-low/elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) as a result of functional somatic inactivation of the DNA MMR protein MSH3 via a nuclear-to-cytosolic displacement. The trigger for MSH3 displacement appears to be inflammation and/or oxidative stress, and unlike MSI-H CRC patients, patients with MSI-L/EMAST CRCs show poor prognosis. These inflammatory-associated microsatellite alterations are a consequence of the local tumor microenvironment, and in theory, if the microenvironment is manipulated to lower inflammation, the microsatellite alterations and MSH3 dysfunction should be corrected. Here we describe the mechanisms and significance of inflammatory-associated microsatellite alterations, and propose three areas to deeply explore the consequences and prevention of inflammation’s effect upon the DNA MMR system.
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