Screening for the Lynch syndrome (Hereditary nonpolyposis colorectal cancer).
Screening for the Lynch syndrome (Hereditary nonpolyposis colorectal cancer).
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DOI：
10.1056/nejmoa043146
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发表时间：
2005-05-05
影响因子：
158.5
通讯作者：
Papadopoulos, N
中科院分区：
文献类型：
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作者：
Hampel, H;Frankel, WL;Papadopoulos, N
背景：错配修复基因MLH1、MSH2、MSH6和PMS2的种系突变会导致林奇综合征（遗传性非息肉病性结直肠癌）的发生，使患者对癌症具有高度易感性。我们评估了结直肠癌患者中此类突变的频率，并研究了分子筛查策略以识别该综合征患者。
方法：在俄亥俄州哥伦布市主要医院新诊断为结直肠腺癌的患者有资格参加本研究。肿瘤微卫星不稳定性的基因分型是主要的筛查方法。在筛查结果显示微卫星不稳定性为阳性的患者中，我们利用错配修复蛋白的免疫组化染色、基因组测序和缺失研究来寻找MLH1、MSH2、MSH6和PMS2基因的种系突变。对突变携带者的家庭成员进行了咨询，对被发现有风险的成员提供了突变检测。
结果：在纳入研究的1066名患者中，208名（19.5%）存在微卫星不稳定性，其中23名患者存在导致林奇综合征的突变（2.2%）。在23名林奇综合征先证者中，10名年龄超过50岁，5名不符合阿姆斯特丹标准或贝塞斯达遗传性非息肉病性结直肠癌诊断指南（包括利用年龄和家族史来识别林奇综合征高风险患者）。仅微卫星不稳定性基因分型和仅免疫组化分析各自未能识别出2名先证者。在21名先证者的家庭中，对117名有风险的人员进行了检测，其中52人有林奇综合征突变，65人没有。
结论：对结直肠腺癌患者进行林奇综合征的常规分子筛查，识别出了患者及其家庭成员中原本无法检测到的突变。这些数据表明，对错配修复蛋白进行免疫组化分析的筛查效果与更复杂的微卫星不稳定性基因分型策略的效果相似。
BACKGROUND:Germ-line mutations in the mismatch-repair genes MLH1, MSH2, MSH6, and PMS2 lead to the development of the Lynch syndrome (hereditary nonpolyposis colorectal cancer), conferring a strong susceptibility to cancer. We assessed the frequency of such mutations in patients with colorectal cancer and examined strategies for molecular screening to identify patients with the syndrome.METHODS:Patients with a new diagnosis of colorectal adenocarcinoma at the major hospitals in metropolitan Columbus, Ohio, were eligible for the study. Genotyping of the tumor for microsatellite instability was the primary screening method. Among patients whose screening results were positive for microsatellite instability, we searched for germ-line mutations in the MLH1, MSH2, MSH6, and PMS2 genes with the use of immunohistochemical staining for mismatch-repair proteins, genomic sequencing, and deletion studies. Family members of carriers of the mutations were counseled, and those found to be at risk were offered mutation testing.RESULTS:Of 1066 patients enrolled in the study, 208 (19.5 percent) had microsatellite instability, and 23 of these patients had a mutation causing the Lynch syndrome (2.2 percent). Among the 23 probands with the Lynch syndrome, 10 were more than 50 years of age and 5 did not meet the Amsterdam criteria or the Bethesda guidelines for the diagnosis of hereditary nonpolyposis colorectal cancer (including the use of age and family history to identify patients at high risk for the Lynch syndrome). Genotyping for microsatellite instability alone and immunohistochemical analysis alone each failed to identify two probands. In the families of 21 of the probands, 117 persons at risk were tested, and of these, 52 had Lynch syndrome mutations and 65 did not.CONCLUSIONS:Routine molecular screening of patients with colorectal adenocarcinoma for the Lynch syndrome identified mutations in patients and their family members that otherwise would not have been detected. These data suggest that the effectiveness of screening with immunohistochemical analysis of the mismatch-repair proteins would be similar to that of the more complex strategy of genotyping for microsatellite instability.