The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas
The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas
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DOI：
10.1086/323658
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发表时间：
2001-10-01
影响因子：
9.8
通讯作者：
Thibodeau, SN
中科院分区：
文献类型：
--
作者：
Cunningham, JM;Kim, CY;Thibodeau, SN
综合分析与DNA错配修复（MMR）基因相关的体细胞和生殖细胞突变可以阐明结直肠癌（CRC）失活的发生率和机制。在本研究中，257例CRC切除术的CRC患者接受了DNA MMR缺陷证据的检查。特别是，我们试图确定在这一队列的患者DNA MMR遗传缺陷的频率。通过检测肿瘤中是否存在hMLH 1、hMSH 2和hMSH 6蛋白表达以及微卫星不稳定性（MSI）来评估MMR状态。在257例患者中，51例（20%）有缺陷MMR的证据，表现出高水平的MSI（MSI-H）和缺乏hMLH 1（n=48）或hMSH 2（n=3）。所有三名缺乏hMSH 2的患者以及一名缺乏hMLH 1的患者也表现出缺乏hMSH 6。对51例MMR缺陷患者的DNA序列分析显示了7个生殖系突变--4个在hMLH 1（2个截短和2个错义），3个在hMSH 2（全部截短）。257例患者中有225例有详细的家族史。在7名有生殖细胞突变的患者中，只有3名有遗传性非息肉病性结直肠癌的家族史。在其余患有MMR缺陷肿瘤的患者中，有8例在hMLH 1中存在体细胞突变。此外，hMLH 1基因启动子的超甲基化存在于37（88%）的42例hMLH 1阴性的情况下进行研究，并在所有的MSI-H肿瘤，显示hMLH 1表达的损失，但没有检测到hMLH 1突变。我们的研究结果表明，虽然有缺陷的DNA MMR发生在20%的大肠癌切除术，遗传性大肠癌由于突变的MMR途径只占一小部分的患者。在257例患者中，只有5例（1.9%）出现明确的MMR遗传缺陷证据。hMLH 1启动子高甲基化的表观遗传（非遗传）机制似乎是大多数剩余患者的肿瘤特征是DNA MMR缺陷的原因。
A comprehensive analysis of somatic and germline mutations related to DNA mismatch-repair (MMR) genes can clarify the prevalence and mechanism of inactivation in colorectal carcinoma (CRC). In the present study, 257 unselected patients referred for CRC resection were examined for evidence of defective DNA MMR. In particular, we sought to determine the frequency of hereditary defects in DNA MMR in this cohort of patients. MMR status was assessed by testing of tumors for the presence or absence of hMLH1, hMSH2, and hMSH6 protein expression and for microsatellite instability (MSI). Of the 257 patients, 51 (20%) had evidence of defective MMR, demonstrating high levels of MSI (MSI-H) and an absence of either hMLH1 (n=48) or hMSH2 (n=3). All three patients lacking hMSH2, as well as one patient lacking hMLH1, also demonstrated an absence of hMSH6. DNA sequence analysis of the 51 patients with defective MMR revealed seven germline mutations-four in hMLH1 (two truncating and two missense) and three in hMSH2 (all truncating). A detailed family history was available for 225 of the 257 patients. Of the seven patients with germline mutations, only three had family histories consistent with hereditary nonpolyposis colorectal cancer. Of the remaining patients who had tumors with defective MMR, eight had somatic mutations in hMLH1. In addition, hypermethylation of the hMLH1 gene promoter was present in 37 (88%) of the 42 hMLH1-negative cases available for study and in all MSI-H tumors that showed loss of hMLH1 expression but no detectable hMLH1 mutations. Our results suggest that, although defective DNA MMR occurs in 20% of unselected patients presenting for CRC resection, hereditary CRC due to mutations in the MMR pathway account for only a small proportion of patients. Of the 257 patients, only 5 (1.9%) appear to have unequivocal evidence of hereditary defects in MMR. The epigenetic (nonhereditary) mechanism of hMLH1 promoter hypermethylation appears to be responsible for the majority of the remaining patients whose tumors are characterized by defective DNA MMR.