Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
Int J Cancer. 2012 May 1;130(9):2088-95. doi: 10.1002/ijc.26233. Epub 2011 Aug 30.
Mutations in the mismatch repair genes cause Lynch syndrome (LS), conferring high risk of colorectal, endometrial and some other cancers. After the same splice site mutation in the MLH1 gene (c.589-2A>G) had been observed in four ostensibly unrelated American families with typical LS cancers, its occurrence in comprehensive series of LS cases (Mayo Clinic, Germany and Italy) was determined. It occurred in 10 out of 995 LS mutation carriers (1.0%) diagnosed in the Mayo Clinic diagnostic laboratory. It did not occur among 1,803 cases tested for MLH1 mutations by the German HNPCC consortium, while it occurred in three probands and an additional five family members diagnosed in Italy. In the U.S., the splice site mutation occurs on a large (∼4.8 Mb) shared haplotype that also harbors the variant c.2146G>A, which predicts a missense change in codon 716 referred to here as V716M. In Italy, it occurs on a different, shorter shared haplotype (∼2.2 Mb) that does not carry V716M. The V716M variant was found to be present by itself in the U.S., German and Italian populations with individuals sharing a common haplotype of 280 kb, allowing us to calculate that the variant arose around 5,600 years ago (225 generations; 95% confidence interval 183-272). The splice site mutation in America arose or was introduced some 450 years ago (18 generations; 95% confidence interval 14-23); it accounts for 1.0% all LS in the Unites States and can be readily screened for.
错配修复基因的突变导致林奇综合征（LS），使结直肠、子宫内膜和其他一些癌症的风险增加。在四个看似无关的美国典型 LS 癌症家族中观察到 MLH1 基因（c.589-2A>G）相同的剪接位点突变后，确定了其在 LS 病例的综合系列中的发生情况（梅奥诊所、德国和意大利）。在梅奥诊所诊断实验室诊断的 995 名 LS 突变携带者中，有 10 人（1.0%）发生了这种突变。在德国 HNPCC 联盟检测的 1803 例 MLH1 突变中，它没有发生，而在意大利的 3 个先证者和另外 5 个家族成员中发生了这种突变。在美国，剪接位点突变发生在一个较大的（约 4.8 Mb）共享单倍型上，该单倍型还携带变体 c.2146G>A，这预示着密码子 716 处的错义变化，这里称为 V716M。在意大利，它发生在一个不同的、较短的共享单倍型（约 2.2 Mb）上，该单倍型不携带 V716M。在美国、德国和意大利人群中，发现 V716M 变体单独存在，这些个体共享一个 280 kb 的共同单倍型，这使我们能够计算出该变体大约在 5600 年前（225 代；95%置信区间 183-272）出现。美国的剪接位点突变是在 450 年前（18 代；95%置信区间 14-23）产生或引入的；它占美国所有 LS 的 1.0%，可以进行简便筛查。
