Immunological Features with DNA Microsatellite Alterations in Patients with Colorectal Cancer.
Immunological Features with DNA Microsatellite Alterations in Patients with Colorectal Cancer.
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DOI：
10.33696/cancerimmunol.2.024
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Carethers JM
中科院分区：
文献类型：
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作者：
Raeker MO;Carethers JM
胜任的人类DNA错配修复（MMR）纠正DNA聚合酶在细胞复制过程中的错误，以维持子细胞中完整的DNA保真度;错误的DNA MMR发生在炎症和肿瘤形成的背景下，在后代细胞中的DNA微卫星序列中产生碱基取代（例如点突变）和移码突变。DNA微卫星序列的移码突变是一种被称为人类疾病微卫星不稳定性（MSI）的检测生物标志物，因为该标志物可以预测和确定癌症患者的治疗方法。有两种类型的MSI：MSI-高（MSI-H），定义为单核苷酸和双核苷酸微卫星序列的移码，以及选定的四核苷酸重复序列或EMAST的升高的微卫星改变，定义为双核苷酸和四核苷酸微卫星序列的移码，但不是单核苷酸序列。患有表现为MSI-H的结直肠癌（CRC）的患者表现出比没有MSI-H肿瘤的患者更好的存活率，这是由来自其序列包含编码微卫星的基因的新型截短蛋白引起的免疫原性新抗原的产生驱动的;这些患者的肿瘤包含数百个体细胞突变，并且显示出对免疫检查点抑制剂治疗的响应性。与没有EMAST肿瘤的患者相比，具有表现出EMAST的CRC的患者表现出较差的存活率，并且可能由归因于MMR蛋白MSH 3超过其移码校正功能的双链断裂修复中的更显性缺陷驱动;这些患者的肿瘤通常含有炎症成分（也称为炎症相关微卫星改变）并且显示较少的体细胞突变和缺乏编码单核苷酸移码突变，所述编码单核苷酸移码突变似乎产生在大多数MSI-H肿瘤中看到的新抗原。总的来说，这两种类型的MSI都是可以诊断CRC患者的生物标志物，可以在标志物组中同时进行检测，并为特定治疗方法提供信息，包括针对癌症的免疫治疗。
Competent human DNA mismatch repair (MMR) corrects DNA polymerase mistakes made during cell replication to maintain complete DNA fidelity in daughter cells; faulty DNA MMR occurs in the setting of inflammation and neoplasia, creating base substitutions (e.g. point mutations) and frameshift mutations at DNA microsatellite sequences in progeny cells. Frameshift mutations at DNA microsatellite sequences are a detected biomarker termed microsatellite instability (MSI) for human disease, as this marker can prognosticate and determine therapeutic approaches for patients with cancer. There are two types of MSI: MSI-High (MSI-H), defined by frameshifts at mono- and di-nucleotide microsatellite sequences, and elevated microsatellite alterations at selected tetranucleotide repeats or EMAST, defined by frameshifts in di- and tetranucleotide microsatellite sequences but not mononucleotide sequences. Patients with colorectal cancers (CRCs) manifesting MSI-H demonstrate improved survival over patients without an MSI-H tumor, driven by the generation of immunogenic neoantigens caused by novel truncated proteins from genes whose sequences contain coding microsatellites; these patients’ tumors contain hundreds of somatic mutations, and show responsiveness to treatment with immune checkpoint inhibitors. Patients with CRCs manifesting EMAST demonstrate poor survival over patients without an EMAST tumor, and may be driven by a more dominant defect in double strand break repair attributed to the MMR protein MSH3 over its frameshift correcting function; these patients’ tumors often have a component of inflammation (and are also termed inflammation-associated microsatellite alterations) and show less somatic mutations and lack coding mononucleotide frameshift mutations that seem to generate the neoantigens seen in the majority of MSI-H tumors. Overall, both types of MSI are biomarkers that can prognosticate patients with CRC, can be tested for simultaneously in marker panels, and informs the approach to specific therapy including immunotherapy for their cancers.