Immunohistochemistry for hMLH1 and hMSH2: A practical test for DNA mismatch repair-deficient tumors
Immunohistochemistry for hMLH1 and hMSH2: A practical test for DNA mismatch repair-deficient tumors
复制标题
DOI：
10.1097/00000478-199910000-00010
复制
发表时间：
1999-10-01
影响因子：
5.6
通讯作者：
Redston, M
中科院分区：
文献类型：
--
作者：
Marcus, VA;Madlensky, L;Redston, M
脱氧核糖核酸（DNA）错配修复基因的失活，最常见的是人类mutL同源物1（hMLH 1）或人类mutS同源物2（hMSH 2），是最近描述的癌症发展和进展的替代途径。由此产生的遗传不稳定性的特征是肿瘤DNA中广泛的体细胞突变，并被称为高频微卫星不稳定性（MSI-H）。尽管在多种肿瘤中有描述，但错配修复缺陷主要在结直肠癌中进行研究。大多数MSI-H结直肠癌是散发性的，但也有一些发生在遗传性非息肉病性结直肠癌（HNPCC）患者中，并且与错配修复基因的种系突变相关。到目前为止，MSI-H癌症的鉴定需要分子检测。为了评价免疫组化作为一种新的错配修复缺陷肿瘤筛查工具的作用，作者研究了hMLH 1和hMSH 2的表达，使用市售的单克隆抗体，在72个福尔马林固定，石蜡包埋的肿瘤中，这些肿瘤先前已经测试过微卫星不稳定性。他们比较了38例MSI-H肿瘤的免疫组化模式，包括16例来自HNPCC患者的已知hMLH 1或hMSH 2生殖系突变，以及34例未显示微卫星不稳定性的肿瘤。38例MSI-H肿瘤中有37例预测有错配修复基因缺陷，表现为hMLH 1和/或hMSH 2表达缺失。这包括与所有16例生殖系突变病例的对应关系。所有34个微卫星稳定的癌症具有两种抗体的完整染色。这些发现清楚地表明，免疫组化可以准确区分MSI-H和微卫星稳定肿瘤，提供了一种具有重要临床和研究应用的实用新技术。
Inactivation of deoxyribonucleic acid (DNA) mismatch repair genes, most commonly human mutL homologue 1 (hMLH1) or human mutS homologue 2 (hMSH2), is a recently described alternate pathway in cancer development and progression. The resulting genetic instability is characterized by widespread somatic mutations in tumor DNA, and is termed high-frequency microsatellite instability (MSI-H). Although described in a variety of tumors, mismatch repair deficiency has been studied predominantly in colorectal carcinoma. Most MSI-H colorectal carcinomas are sporadic, but some occur in patients with hereditary nonpolyposis colorectal cancer (HNPCC), and are associated with germline mutations in mismatch repair genes. Until now, the identification of MSI-H cancers has required molecular testing. To evaluate the role of immunohistochemistry as a new screening tool for mismatch repair-deficient neoplasms, the authors studied the expression of hMLH1 and hMSH2, using commercially available monoclonal antibodies, in 72 formalin-fixed, paraffin-embedded tumors that had been tested previously for microsatellite instability. They compared immunohistochemical patterns of 38 MSI-H neoplasms, including 16 cases from HNPCC patients with known germline mutations in hMLH1 or hMSH2, with 34 neoplasms that did not show microsatellite instability. Thirty-seven of 38 MSI-H neoplasms were predicted to have a mismatch repair gene defect, as demonstrated by the absence of hMLH1 and/or hMSH2 expression. This included correspondence with all 16 cases with germline mutations. All 34 microsatellite-stable cancers had intact staining with both antibodies. These findings clearly demonstrate that immunohistochemistry can discriminate accurately between MSI-H and microsatellite-stable tumors, providing a practical new technique with important clinical and research applications.