Deficient DNA mismatch repair:: a common etiologic factor for colon cancer
Deficient DNA mismatch repair:: a common etiologic factor for colon cancer
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DOI：
10.1093/hmg/10.7.735
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发表时间：
2001-04-01
影响因子：
3.5
通讯作者：
Peltomäki, P
中科院分区：
文献类型：
--
作者：
Peltomäki, P
遗传性非息肉病性结肠癌（HNPCC）是遗传性结肠癌最常见的形式，是一种DNA错配修复缺陷综合征（MMR），已经鉴定出五种，可能是六种人类MMR基因，当在种系中发生突变时，导致对这种综合征的易感性。迄今为止，已知超过300种不同的易感突变，主要影响MMR基因MLH1（相似50%），MSH2（相似40%）和MSH6（相似10%）。遗传易感个体在每个细胞中都携带MMR基因的缺陷拷贝，靶组织（通常是结肠）中剩余的野生型拷贝的体细胞失活导致深刻的修复缺陷，突变的进行性积累和癌症，短串联重复序列的不稳定性。微卫星是MMR缺乏的典型表现，除HNPCC肿瘤外，约15%的散发性结肠癌和其他肿瘤发生微卫星。大多数后一种病例可归因于一个特定的MMR基因MLH1，与HNPCC不同，表观遗传机制而不是遗传机制在该基因失活中起重要作用。最近的发现表明，除了复制后修复之外，MMR蛋白还有其他几种与癌变高度相关的功能。了解MMR系统与其他细胞通路之间复杂的相互作用，使我们能够更好地理解HNPCC和其他MMR缺陷癌症的表型表现。
Hereditary non-polyposis colon cancer (HNPCC), the most common form of hereditary colon cancer, is a syndrome of deficient DNA mismatch repair (MMR), Five, possibly six, human MMR genes have been identified that, when mutated in the germline, cause susceptibility to this syndrome. To date, more than 300 different predisposing mutations are known, mainly affecting the MMR genes MLH1 (similar to 50%), MSH2 (similar to 40%) and MSH6 (similar to 10%), Genetically predisposed individuals carry a defective copy of an MMR gene in every cell, Somatic inactivation of the remaining wild-type copy in a target tissue, typically colon, gives rise to a profound repair defect, progressive accumulation of mutations and cancer, Instability at short tandem repeat sequences, microsatellites, is a typical manifestation of MMR deficiency and apart from HNPCC tumors, occurs in similar to 15% of sporadic colon and other tumors. The majority of the latter cases are attributable to one particular MMR gene, MLH1, and unlike HNPCC, an epigenetic rather than a genetic mechanism plays an important role in the inactivation of this gene. The present review provides an update of the genetics of HNPCC and more generally, of cancer development driven by deficient MMR, Recent discoveries suggest that apart from post-replication repair, MMR proteins have several other functions that are highly relevant to carcinogenesis, Knowledge of the complex interplay between the MMR system and other cellular pathways allows us to better understand the phenotypic manifestations of HNPCC and other cancers with deficient MMR.