Gologan Adrian, Sepulveda Antonia R
Department of Pathology, University of Pittsburgh, PUH-A610, 100 Lothrop Street, Pittsburgh, PA 15213-2582, USA.
Clin Lab Med. 2005 Mar;25(1):179-96. doi: 10.1016/j.cll.2004.12.001.
The reference cancers associated with DNA mismatch repair (MMR)deficiency are the adenocarcinomas of patients with hereditary nonpolyposis colorectal cancer, also known as Lynch syndrome. Sporadic gastrointestinal (GI) carcinomas, most commonly colorectal and gastric carcinomas, may also be associated with deficiencies of DNA mismatch repair. Deficiency in cellular MMR leads to wide-spread mutagenesis and neoplastic development and progression. An important diagnostic feature of MMR-deficient tumors is the high rate of mutations that accumulate in repetitive nucleotide regions, and these mutations are known as microsatellite instability(MSI). A standard panel of markers to test for MSI in tumors has been recommended and efficiently separates tumors into those with high, low, or no microsatellite instability (MSI-H, MSI-L, or MSS). Tumors characterized by MSI-H characteristically show loss of one of the main DNA MMR proteins, mLH1 or MSH2, and rarely MSH6 and PMS2, detected by immunohistochemistry (IHC). The combination of MSI testing and IHC for MMR proteins in tumors tissues is used to identify underlying DNA MMR deficiency andis clinically relevant screen patients who might have hereditary non-polyposis colorectal cancer for DNA repair gene germline testing. Increasing evidence demonstrates that tumors with a positive MSI status have lower lymph node metastases burden, and these patients have an overall improved survival, suggesting that the MSI and MMR status may contribute to decision making regarding treatment approaches. Updated guidelines for MSI and IHC for DNAMMR testing, and the biological and potential clinical implications of MMR deficiency and microsatellite instability in GI polyps and cancers are reviewed.
与DNA错配修复（MMR）缺陷相关的参考癌症是遗传性非息肉病性结直肠癌患者的腺癌，也称为林奇综合征。散发性胃肠道（GI）癌，最常见的是结直肠癌和胃癌，也可能与DNA错配修复缺陷有关。细胞MMR缺陷会导致广泛的诱变以及肿瘤的发生和发展。MMR缺陷肿瘤的一个重要诊断特征是在重复核苷酸区域积累的高突变率，这些突变被称为微卫星不稳定性（MSI）。已经推荐了一组用于检测肿瘤中MSI的标准标志物，并且可以有效地将肿瘤分为微卫星不稳定性高、低或无（MSI-H、MSI-L或MSS）的肿瘤。以MSI-H为特征的肿瘤通常显示主要DNA MMR蛋白之一（mLH1或MSH2）缺失，很少有MSH6和PMS2缺失，可通过免疫组织化学（IHC）检测到。肿瘤组织中MSI检测和MMR蛋白的IHC相结合，用于识别潜在的DNA MMR缺陷，并在临床上筛选可能患有遗传性非息肉病性结直肠癌的患者进行DNA修复基因种系检测。越来越多的证据表明，MSI状态为阳性的肿瘤淋巴结转移负担较低，这些患者的总体生存率有所提高，这表明MSI和MMR状态可能有助于治疗方法的决策。本文综述了DNA MMR检测的MSI和IHC的更新指南，以及GI息肉和癌症中MMR缺陷和微卫星不稳定性的生物学及潜在临床意义。
