Thibodeau S N, French A J, Roche P C, Cunningham J M, Tester D J, Lindor N M, Moslein G, Baker S M, Liskay R M, Burgart L J, Honchel R, Halling K C
Department of Laboratory Medicine and Pathology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.
Cancer Res. 1996 Nov 1;56(21):4836-40.
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.
迄今为止，已证实在遗传性非息肉病性结肠癌患者的种系中，至少有四个参与DNA错配修复（MMR）的基因发生了改变：hMSH2、hMLH1、hPMS1和hPMS2。此外，已证实MMR功能丧失会导致这些患者肿瘤中出现微卫星不稳定性（MIN）现象。在本研究中，我们通过免疫组织化学检测了7例MIN+散发性癌患者、13例家族性结直肠癌患者以及12例符合遗传性非息肉病性结肠癌严格阿姆斯特丹标准患者的石蜡包埋肿瘤中hMSH2和hMLH1的蛋白表达模式。研究了这两种基因产物的表达、种系或体细胞突变的存在与肿瘤MIN存在之间的关系。在所研究的28个肿瘤中，19个显示出MIN，而分别在6例和2例患者中检测到hMLH1和hMSH2的突变。在8例MIN+/突变+病例中，除1例（hMLH1错义突变）外，所有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-病例也显示hMLH1（n = 5）、hMSH2（n = 1）或两者（n = 1）均无表达，而4例MIN+/突变-病例则显示两者表达正常。所有MIN-/突变-病例（n = 9）均未显示任何一种蛋白的表达模式改变。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预筛肿瘤MMR基因突变的方法。
