LOSS OF THE WILD-TYPE MLH1 GENE IS A FEATURE OF HEREDITARY NONPOLYPOSIS COLORECTAL-CANCER
LOSS OF THE WILD-TYPE MLH1 GENE IS A FEATURE OF HEREDITARY NONPOLYPOSIS COLORECTAL-CANCER
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DOI：
10.1038/ng1294-405
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发表时间：
1994-12-01
期刊：
影响因子：
30.8
通讯作者：
AALTONEN, LA
中科院分区：
文献类型：
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作者：
HEMMINKI, A;PELTOMAKI, P;AALTONEN, LA
DNA错配修复基因的生殖系突变导致肿瘤形成的易感性的机制尚不清楚。体外研究表明，与纯合性不同，这些突变的杂合性不影响错配修复。令人惊讶的是，迄今为止，在遗传性非息肉病性结直肠癌中还没有发现易感基因座的杂合性丢失。在这里，我们表明，杂合性丢失（洛）的标记内或附近的MLH 1基因的染色体3 p发生非随机的肿瘤，从家庭成员的疾病表型与MLH 1共分离。在每一个信息的情况下，损失影响野生型等位基因。这些结果表明，DNA错配修复基因类似于肿瘤抑制基因，需要两次命中才能引起表型效应。
The mechanism by which germline mutations of DNA mismatch repair genes cause susceptibility to tumour formation is not yet understood. Studies in vitro indicate that heterozygosity for these mutations, unlike homozygosity, does not affect mismatch repair. Surprisingly, no loss of heterozygosity at the predisposing loci has so far been described in hereditary nonpolyposis colorectal cancers. Here, we show that loss of heterozygosity (LOH) of markers within or adjacent to the MLH1 gene on chromosome 3p occurs nonrandomly in tumours from members of families in which the disease phenotype cosegregates with MLH1. In every informative case, the loss affects the wild type allele. These results suggest that DNA mismatch repair genes resemble tumour suppressor genes in that two hits are required to cause a phenotypic effect.