Microsatellite instability analysis and/or immunostaining for the diagnosis of hereditary nonpolyposis colorectal cancer?
Microsatellite instability analysis and/or immunostaining for the diagnosis of hereditary nonpolyposis colorectal cancer?
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DOI：
10.1007/s00428-003-0922-z
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发表时间：
2004-02-01
期刊：
影响因子：
3.5
通讯作者：
Nilbert, M
中科院分区：
文献类型：
--
作者：
Halvarsson, B;Lindblom, A;Nilbert, M
遗传性非息肉病性结直肠癌（HNPCC）占结直肠癌的2-4%，由错配修复（MMR）基因的结构性缺陷引起，最常见的影响基因是MLH1、MSH2和MSH6。MMR缺陷导致癌症风险增加，终生风险最大的是结直肠癌和子宫内膜癌。hnpcc相关的肿瘤表型通常以微卫星不稳定性（MSI）和受影响的MMR蛋白的免疫组织化学表达缺失为特征。我们对128例疑似HNPCC患者肿瘤中MLH1、MSH2和MSH6的MSI分析和免疫染色获得的信息进行了评估。128例肿瘤中有59例（46%）存在msi高模式。在59例可评估的MSI肿瘤中，有54例（92%）发现至少一种MMR蛋白的免疫组织化学表达缺失。这种缺失影响了28例MLH1、22例MSH2和21例MSH6（其中4例肿瘤中仅有MSH6缺失）。5例MMR蛋白表达正常（8%）。69例微卫星稳定型或低msi肿瘤均显示三种蛋白的免疫染色正常。在所有MSI-H肿瘤的28例患者中，MLH1、MSH2或MSH6的种系突变已经被鉴定出来，并且在所有这些病例中都鉴定出相应的MMR蛋白表达的免疫组织化学损失。总之，MMR蛋白MLH1、MSH2和MSH6的免疫染色检测MMR缺陷肿瘤的敏感性为92%，特异性为100%。MMR蛋白免疫染色有助于疑似HNPCC患者的突变分析，因为它可以精确定位突变基因，但在MMR蛋白表达保留的MSI肿瘤的遗传背景明确之前，我们建议MSI和MMR蛋白免疫染色在临床HNPCC分析中最好结合使用。
Hereditary nonpolyposis colorectal cancer (HNPCC) represents 2-4% of colorectal cancers and is caused by a constitutional defect in a mismatch repair (MMR) gene, most commonly affecting the genes MLH1, MSH2, and MSH6. The MMR defect results in an increased cancer risk with the greatest lifetime risks for colorectal cancer and endometrial cancer. The HNPCC-associated tumor phenotype is generally characterized by microsatellite instability (MSI) and immunohistochemical loss of expression of the affected MMR protein. We have evaluated the information obtained from MSI analysis and immunostaining for MLH1, MSH2, and MSH6 in a series of 128 tumors from patients suspected of having HNPCC. A MSI-high pattern was present in 59 of 128 (46%) tumors. Loss of immunohistochemical expression for at least one of these MMR proteins was found in 54 of 59 (92%) evaluable MSI tumors. This loss affected MLH1 in 28, MSH2 in 22, and MSH6 in 21 tumors (with MSH6 as the only loss in 4 tumors). Five (8%) MSI-high tumors showed normal MMR protein expression. All 69 microsatellite stable or MSI-low tumors showed normal immunostaining for all three proteins. In 28 patients, all with MSI-H tumors, germ-line mutations of MLH1, MSH2, or MSH6 had been identified, and a corresponding immunohistochemical loss of MMR protein expression was identified in all these cases. In summary, immunostaining for the MMR proteins MLH1, MSH2, and MSH6 had a sensitivity of 92% and a specificity of 100% for detecting MMR-deficient tumors. MMR protein immunostaining facilitates mutation analysis in suspected HNPCC patients, since it pinpoints the mutated gene, but until the genetic background to the MSI tumors with retained MMR protein expression has been clarified, we suggest that MSI and MMR protein immunostaining should optimally be combined in clinical HNPCC analysis.