Prediction of MLH1 and MSH2 mutations in Lynch syndrome
Prediction of MLH1 and MSH2 mutations in Lynch syndrome
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DOI：
10.1001/jama.296.12.1469
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发表时间：
2006-09-27
影响因子：
120.7
通讯作者：
Syngal, Sapna
中科院分区：
文献类型：
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作者：
Balmana, Judith;Stockwell, David H.;Syngal, Sapna
背景 林奇综合征主要由错配修复基因 MLH1 和 MSH2 的突变引起。 目标 分析一大群接受基因检测的患者中 MLH1/MSH2 突变的患病率，并开发一个临床模型来预测在高危患者中发现突变的可能性。 设计、设置和参与者 获得了 1914 名无关先证者的个人和家族史，这些先证者从 2000 年开始提交了血液样本，以进行全基因测序。 MLH1/MSH2。结合序列分析和Southern印迹进行遗传分析。在 898 名个体的初始队列中使用逻辑回归开发了多变量模型，随后在 1016 名患者中进行了前瞻性验证。我们命名为 PREMM1,2（MLH1 和 MSH2 突变预测）的复杂模型被开发成一个基于网络的工具，其中包含个人和家族癌症和腺瘤史。主要结果测量 MLH1/MSH2 基因中的有害突变。结果总体而言，14.5% 的先证者 (130/898) 携带致病性突变（MLH1，6.5%；MSH2， 8.0%）在开发队列中，15.3%（155/1016）在验证队列中，后者中有 42 个（27%）是大的重排。突变的强预测因素包括先证者特征（结直肠癌的存在，特别是> = 2次单独的诊断，或子宫内膜癌）和家族史（特别是患有结直肠癌或子宫内膜癌的一级亲属的数量）。诊断时的年龄对于结直肠癌尤其重要。多变量模型在外部验证中具有良好的区分性，受试者工作特征曲线下面积为 0.80（95% 置信区间，0.76-0.84）。 结论 个人和家族史特征可以准确预测大量林奇综合征风险人群的基因检测结果。 PREMM1,2 模型为临床医生提供了一个客观、易于使用的工具来估计在 MLH1/MSH2 基因中发现突变的可能性，并可以指导分子评估策略。
Context Lynch syndrome is caused primarily by mutations in the mismatch repair genes MLH1 and MSH2.Objectives To analyze MLH1/MSH2 mutation prevalence in a large cohort of patients undergoing genetic testing and to develop a clinical model to predict the likelihood of finding a mutation in at-risk patients.Design, Setting, and Participants Personal and family history were obtained for 1914 unrelated probands who submitted blood samples starting in the year 2000 for full gene sequencing of MLH1/MSH2. Genetic analysis was performed using a combination of sequence analysis and Southern blotting. A multivariable model was developed using logistic regression in an initial cohort of 898 individuals and subsequently prospectively validated in 1016 patients. The complex model that we have named PREMM1,2 (Prediction of Mutations in MLH1 and MSH2) was developed into a Web-based tool that incorporates personal and family history of cancer and adenomas.Main Outcome Measure Deleterious mutations in MLH1/MSH2 genes.Results Overall, 14.5% of the probands (130/898) carried a pathogenic mutation (MLH1, 6.5%; MSH2, 8.0%) in the development cohort and 15.3% (155/1016) in the validation cohort, with 42 (27%) of the latter being large rearrangements. Strong predictors of mutations included proband characteristics (presence of colorectal cancer, especially >= 2 separate diagnoses, or endometrial cancer) and family history (especially the number of first-degree relatives with colorectal or endometrial cancer). Age at diagnosis was particularly important for colorectal cancer. The multivariable model discriminated well at external validation, with an area under the receiver operating characteristic curve of 0.80 (95% confidence interval, 0.76-0.84).Conclusions Personal and family history characteristics can accurately predict the outcome of genetic testing in a large population at risk of Lynch syndrome. The PREMM1,2 model provides clinicians with an objective, easy-to-use tool to estimate the likelihood of finding mutations in the MLH1/MSH2 genes and may guide the strategy for molecular evaluation.