Missense mutations in hMLH1 associated with colorectal cancer
Missense mutations in hMLH1 associated with colorectal cancer
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DOI：
10.1007/s004390051127
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发表时间：
1999-11-01
期刊：
影响因子：
5.3
通讯作者：
Lindblom, A
中科院分区：
文献类型：
--
作者：
Liu, T;Tannergård, P;Lindblom, A
与结直肠癌相关的最普遍的遗传综合征之一是遗传性非息肉病性结直肠癌（HNPCC）。HNPCC的遗传基因缺陷被证明存在于DNA错配修复基因中，主要是hMSH2或hMLH1。大多数HN-PCC患者的相关错配修复基因是杂合的；它们有一个正常的和一个突变的等位基因，在正常体细胞中错配修复是有功能的。HNPCC的癌症易感性被认为与体细胞中野生型等位基因的缺失有关，导致DNA错配修复缺陷。这导致了DNA微卫星不稳定性（MSI），增加了体细胞突变率，并最终导致了参与结直肠癌发生的基因突变的积累。为了支持这一理论，HNPCC患者和hMSH2或hMLH1缺失小鼠的结直肠肿瘤显示MSI。在这里，我们描述了与结直肠癌相关的hMLH1外显子16的两个错义突变。有趣的是，肿瘤未显示MSI。这引发了一些潜在的重要问题。首先，即使是微卫星阴性的结直肠肿瘤也可能与种系突变有关，如果使用MST检测来选择患者进行突变筛查，这些突变将被遗漏。其次，这些病例中缺乏MSI表明致癌机制可能与通常假设的不同。
One of the most prevalent hereditary syndromes associated with colorectal cancer is hereditary nonpolyposis colorectal cancer (HNPCC). The inherited gene defects in HNPCC have been shown to reside in DNA mismatch repair genes, mostly hMSH2 or hMLH1. Most HN-PCC patients are heterozygous with regard to the relevant mismatch repair gene; they have one normal and one mutated allele, and mismatch repair in normal somatic cells is functional. Cancer predisposition in HNPCC is believed to be associated with the loss of the wild-type allele in somatic cells, resulting in defective DNA mismatch repair. This gives rise to DNA microsatellite instability (MSI), an increased somatic mutation rate, and eventually to the accumulation of mutations in genes involved in colorectal carcinogenesis. In support of this theory, colorectal tumors in HNPCC patients and in mice deficient for hMSH2 or hMLH1 show MSI. Here, we describe two missense mutations in hMLH1 exon 16 associated with colorectal cancer. Interestingly, the tumors do not show MSI. This raises some potentially important issues. First, even microsatellite-negative colorectal tumors can be associated with germline mutations and these will be missed if an MST test is used to select patients for mutation screening. Second, the lack of MSI in these cases suggests that the mechanism involved in carcinogenesis could be different from that generally hypothesized.