Causes of microsatellite instability in colorectal tumors: implications for hereditary non-polyposis colorectal cancer screening
Causes of microsatellite instability in colorectal tumors: implications for hereditary non-polyposis colorectal cancer screening
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DOI：
10.1016/s0165-4608(00)00399-x
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发表时间：
2001-04-15
影响因子：
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通讯作者：
Ravnik-Glavac, M
中科院分区：
文献类型：
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作者：
Potocnik, U;Glavac, D;Ravnik-Glavac, M
采用微卫星标记的“参考组”对345例原发性结直肠癌（CRC）进行了微卫星不稳定性（MSI）分析。35例（10%）肿瘤被归类为高MSI（MSI-H）。我们确定了6例（17%）MSI-H肿瘤在错配修复中存在种系突变。(MMR)29例（83%）MSI-H肿瘤无生殖系MMR突变（散发性MSI-H肿瘤）。在26/29例（90%）散发性MSI-H肿瘤中发现hMLH 1启动子的高甲基化，但仅在1/6例（17%）HNPCC肿瘤中发现（P <0.001）。在HNPCC肿瘤中的两个MMR基因中都发现了体细胞改变，但在散发性MSI-H肿瘤中主要是hMSH 2基因。在3/6例（50%）HNPCC肿瘤和4/26例（15%）散发性MSI-H突变中检测到MMR位点的洛缺失。这些结果共同表明散发性MSI-H肿瘤与HNPCC患者的MSI-H肿瘤中MMR基因的失活模式不同。因此，我们建议，在MSI-W肿瘤中进行MSI分析，然后进行hMLH 1启动子甲基化分析，以及在缺乏hMLH 1启动子甲基化的MSI-H肿瘤中进行MMR基因突变分析，这可能是HNPCC筛查的有效分子遗传学方法。(C)2001 Elsevier Science Inc. All rights reserved.
Microsatellite instability (MSI) analysis was performed using a "reference panel" of microsatellite markers in 345 unselected primary colorectal cancers (CRC). Thirty-five (10%) tumors were classified as high MSI (MSI-H). We identified 6 (17%) MSI-H tumors with germline mutations in mis match repair. (MMR) genes (tumors from patients with hereditary non-polyposis colorectal cancer (HNPCC) syndrome) and 29 (83%) MSI-H tumors without germline MMR mutations (sporadic MSI-H tumors). Hypermethylation of the hMLH1 promoter was found in 26/29 (90%) sporadic MSI-H tumors but only in 1/6 (17%) HNPCC tumors (P < .001). Somatic alterations were identified in both MMR genes in HNPCC tumors but mainly in the hMSH2 gene in sporadic MSI-H tumors. LOH at MMR loci was detected in 3/6 (50%) HNPCC tumors and in 4/26 (15%) informative sporadic MSI-H turners. These results together indicate different mode of inactivation of MMR genes in sporadic MSI-H tumors versus MSI-H tumors in HNPCC patients. We therefore propose that MSI analysis of newly diagnosed primary CRC followed by methylation analysis of hMLH1 promoter in MSI-W tumors and mutational analysis of MMR genes in MSI-H tumors lacking hMLH1 promoter methylation might be an efficient molecular genetic approach for HNPCC screening. (C) 2001 Elsevier Science Inc. All rights reserved.