The role of MLH1, MSH2 and MSH6 in the development of multiple colorectal cancers.
The role of MLH1, MSH2 and MSH6 in the development of multiple colorectal cancers.
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MLH1，MSH2和MSH6在多种结直肠癌的发展中的作用。
DOI：
10.1038/sj.bjc.6602708
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发表时间：
2005-08-22
影响因子：
8.8
通讯作者：
Boulos, PB
中科院分区：
文献类型：
--
作者：
Lawes, DA;Pearson, T;SenGupta, S;Boulos, PB
微卫星不稳定性（MSI）的发生率增加的患者谁发展多原发性结直肠癌（CRC），虽然与遗传性非息肉病性结肠癌（HNPCC）的关联尚不清楚。本研究旨在评估这些患者MSI的潜在遗传原因。研究了111个石蜡包埋的CRC的微卫星不稳定性，这些CRC来自78例异时性和同步性癌症患者，对照组由74例来自单个CRC患者的癌症组成。肿瘤分为高水平（MSI-H）、低水平（MSI-L）或稳定（MSS）。免疫组化法检测MLH 1、MSH 2和MSH 6基因表达。在不能表达MLH 1的MSI-H癌症中评估MLH 1启动子区域的甲基化，并在表达MLH 1、MSH 2和MSH 6蛋白的MSI-H样品中进行突变分析。多发癌中MSI-H的发生率为52%（58/111），而单发癌中MSI-H的发生率为13.5%（10/74），两者差异有统计学意义（P<0.01）。在分析了两种或多种癌症的32名患者中，8名（25%）在两种癌症中均表现出MSI-H，13名（41%）在一种癌症中表现出MSI-H，11名（34%）未能表现出任何MSI-H。MSI-H单一癌症在9个病例中的7个（78%）中不表达MLH 1或MSH 2，MSI-L/MSS癌症在45个病例中的1个（2.2%）中不表达MLH 1或MSH 2，所有癌症表达MSH 6。43例MSI-H多发癌中有21例（48%）不表达MLH 1或MSH 2，32例MSI-L/MSS癌中有4例（12.5%）不表达MLH 1或MSH 2。MSH 6表达在5例MSI-H多发性癌症中丢失，其中4例也未能表达MLH 1或MSH 2。19名患者中有6名（31%）在两种癌症中发现了相同的错配修复（MMR）基因表达缺失。在未能表达MLH 1的17例多发性MSI-H癌症中的11例（65%）和6例单一MSI-H癌症中的3例（50%）中鉴定出甲基化。对10例表达MLH 1、MSH 2和MSH 6的MSI-H多发性癌症的突变分析未能证实MLH 1或MSH 2基因的突变。我们认为，尽管MSI-H在多发性结直肠癌患者中更常见，但这通常不是由经典的HNPCC途径引起的。
There is increased incidence of microsatellite instability (MSI) in patients who develop multiple primary colorectal cancers (CRC), although the association with hereditary nonpolyposis colon cancer (HNPCC) is unclear. This study aims to evaluate the underlying genetic cause of MSI in these patients. Microsatellite instability was investigated in 111 paraffin-embedded CRCs obtained from 78 patients with metachronous and synchronous cancers, and a control group consisting of 74 cancers from patients with a single CRC. Tumours were classified as high level (MSI-H), low level (MSI-L) or stable (MSS). MLH1, MSH2 and MSH6 gene expression was measured by immunohistochemistry. Methylation of the MLH1 promoter region was evaluated in MSI-H cancers that failed to express MLH1, and mutational analysis performed in MSI-H samples that expressed MLH1, MSH2 and MSH6 proteins. The frequency of MSI-H was significantly greater in the multiple, 58 out of 111 (52%), compared to the single cancers, 10 out of 74 (13.5%), P<0.01. Of the 32 patients from whom two or more cancers were analysed, eight (25%) demonstrated MSI-H in both cancers, 13 (41%) demonstrated MSI-H in one cancer and 11 (34%) failed to demonstrate any MSI-H. MSI-H single cancers failed to express MLH1 or MSH2 in seven out of nine (78%) cases and MSI-L/MSS cancers failed to express MLH1 or MSH2 in one out of 45 (2.2%) cases, all cancers expressed MSH6. MSI-H multiple cancers failed to express MLH1 or MSH2 in 21 out of 43 (48%) cases and MSI-L/MSS cancers failed to express MLH1 or MSH2 in four out of 32 (12.5%) cases. MSH6 expression was lost in five MSI-H multiple cancers, four of which also failed to express MLH1 or MSH2. Loss of expression of the same mismatch repair (MMR) gene was identified in both cancers from six out of 19 (31%) patients. Methylation was identified in 11 out of 17 (65%) multiple and three out of six (50%) single MSI-H cancers that failed to express MLH1. Mutational analysis of 10 MSI-H multiple cancers that expressed MLH1, MSH2 and MSH6 failed to demonstrate mutations in the MLH1 or MSH2 genes. We suggest that, although MSI-H is more commonly identified in those with multiple colorectal cancers, this does not commonly arise from a classical HNPCC pathway.
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影响因子：
9.6
作者：
Beck, NE;Tomlinson, IPM;Bodmer, WF
通讯作者：
Bodmer, WF
影响因子：
45.3
作者：
Percesepe, A;Borghi, F;de Leon, MP
通讯作者：
de Leon, MP
影响因子：
--
作者：
Potocnik, U;Glavac, D;Ravnik-Glavac, M
通讯作者：
Ravnik-Glavac, M
影响因子：
29.4
作者：
Samowitz, WS;Curtin, K;Slattery, ML
通讯作者：
Slattery, ML
影响因子：
158.5
作者：
Aaltonen, LA;Salovaara, R;ValKamo, E
通讯作者：
ValKamo, E