HEREDITARY, SPORADIC AND METASTATIC COLORECTAL CANCER ARE COMMONLY DRIVEN BY SPECIFIC SPECTRUMS OF DEFECTIVE DNA MISMATCH REPAIR COMPONENTS.
HEREDITARY, SPORADIC AND METASTATIC COLORECTAL CANCER ARE COMMONLY DRIVEN BY SPECIFIC SPECTRUMS OF DEFECTIVE DNA MISMATCH REPAIR COMPONENTS.
复制标题
DOI：
--
复制
发表时间：
2016
影响因子：
--
通讯作者：
J. Carethers
中科院分区：
文献类型：
--
作者：
J. Carethers
DNA错配修复（MMR）是用于修复DNA内可变错误的几种人类细胞机制之一，特别是在DNA复制后。MMR功能依赖于特定MMR蛋白的异二聚化，其可以识别碱基-碱基错配以及微卫星序列的移码，随后触发其他互补蛋白，其执行切除和修复或在修复无效时启动细胞死亡。MMR功能在特定疾病状态下受损，所有这些都可以通过微卫星序列的错误修复进行生化识别，导致微卫星不稳定性。MMR基因的种系突变导致Lynch综合征，这是最常见的遗传性结直肠癌（CRC），双等位基因种系突变导致罕见的体质性错配修复缺陷综合征。在15%的散发性CRC中观察到通过表观遗传机制的MMR体细胞失活，并且一小部分CRC具有双等位基因体细胞突变。在高达60%的散发性CRC中观察到特异性MMR蛋白hMSH 3的新型炎症驱动的核至胞质转变，其与转移和患者预后不良相关，这与MMR基因失活时的改善结果不同。MMR失活的机制以及受影响的组分决定了患者的临床谱和临床反应。
DNA mismatch repair (MMR) is one of several human cell mechanisms utilized to repair mutable mistakes within DNA, particularly after DNA is replicated. MMR function is dependent upon heterodimerization of specific MMR proteins that can recognize base-base mispairs as well as frameshifts at microsatellite sequences, followed by the triggering of other complementary proteins that execute excision and repair or initiate cell demise if repair is futile. MMR function is compromised in specific disease states, all of which can be biochemically recognized by faulty repair of microsatellite sequences, causing microsatellite instability. Germline mutation of an MMR gene causes Lynch syndrome, the most common inherited form of colorectal cancer (CRC), and biallelic germline mutations cause the rare constitutional mismatch repair deficiency syndrome. Somatic inactivation of MMR through epigenetic mechanisms is observed in 15% of sporadic CRC, and a smaller portion of CRCs possess biallelic somatic mutations. A novel inflammation-driven nuclear-to-cytoplasmic shift of the specific MMR protein hMSH3 is seen in up to 60% of sporadic CRCs that associates with metastasis and poor patient prognosis, unlike improved outcome when MMR is genetically inactivated. The mechanism for MMR inactication as well as the component affected dictates the clinical spectrum and clinical response for patients.