Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes.
Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes.
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发表时间：
1996-11
期刊：
影响因子：
11.2
通讯作者：
S. Thibodeau;A. French;P. Roche;J. Cunningham;D. Tester;N. Lindor;G. Möslein;S. Baker;R. Liskay-R
中科院分区：
文献类型：
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作者：
S. Thibodeau;A. French;P. Roche;J. Cunningham;D. Tester;N. Lindor;G. Möslein;S. Baker;R. Liskay-R
迄今为止，至少有四个参与DNA错配修复（MMR）的基因已被证明在遗传性非息肉病性结肠癌患者的种系中发生改变：hMSH2、hMLH1、hPMS1和hPMS2。此外，MMR功能的丧失已被证明会导致这些患者肿瘤中的微卫星不稳定性（MIN）现象。在本研究中，我们通过免疫组织化学方法检测了7例MIN+散发性癌、13例家族性结直肠癌和12例符合严格的阿姆斯特丹标准的遗传性非息肉性结肠癌石蜡包埋肿瘤中hMSH2和hMLH1的蛋白表达模式。研究了这两个基因产物的表达、种系或体细胞突变的存在以及肿瘤MIN的存在之间的关系。研究的28例肿瘤中有19例显示MIN，而hMLH1和hMSH2分别在6例和2例患者中检测到突变。在8例MIN+/突变+病例中，除一例（hMLH1错义突变）外，其余病例均未观察到相应基因产物的蛋白表达。然而，7例MIN+/突变病例也未表现出hMLH1 （n = 5）、hMSH2 （n = 1）或两者均不表达（n = 1），而4例MIN+/突变病例均表现出正常表达。没有一例MIN-/突变病例（n = 9）显示两种蛋白的表达模式发生改变。这些数据表明，通过免疫组织化学检测蛋白表达可能是一种快速筛选肿瘤中MMR基因突变的方法。
To date, at least four genes involved in DNA mismatch repair (MMR) have been demonstrated to be altered in the germline of patients with hereditary nonpolyposis colon cancer: hMSH2, hMLH1, hPMS1, and hPMS2. Additionally, loss of MMR function has been demonstrated to lead to the phenomenon of microsatellite instability (MIN) in tumors from these patients. In this study, we have examined the protein expression pattern of hMSH2 and hMLH1 by immunohistochemistry in paraffin-embedded tumors from 7 patients with MIN+ sporadic cancer, 13 patients with familial colorectal cancer, and 12 patients meeting the strict Amsterdam criteria for hereditary nonpolyposis colon cancer. The relationship between the expression of these two gene products, the presence of germline or somatic mutations, and the presence of tumor MIN was examined. Nineteen of the 28 tumors studied demonstrated MIN, whereas mutations in hMLH1 and hMSH2 were detected in 6 and 2 patients, respectively. Of the eight MIN+/mutation+ cases, the absence of protein expression was observed for the corresponding gene product in all but one case (missense mutation in hMLH1). However, seven MIN+/mutation- cases also showed no expression of either hMLH1 (n = 5), hMSH2 (n = 1), or both (n = 1), whereas four MIN+/mutation- cases demonstrated normal expression for both. None of the MIN-/mutation- cases (n = 9) demonstrated an altered expression pattern for either protein. These data suggest that examination of protein expression by immunohistochemistry may be a rapid method for prescreening tumors for mutations in the MMR genes.