MLH1 promoter hypermethylation in the analytical algorithm of Lynch syndrome: a cost-effectiveness study
MLH1 promoter hypermethylation in the analytical algorithm of Lynch syndrome: a cost-effectiveness study
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DOI：
10.1038/ejhg.2011.277
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发表时间：
2012-07-01
影响因子：
5.2
通讯作者：
Capella, Gabriel
中科院分区：
文献类型：
--
作者：
Gausachs, Mireia;Mur, Pilar;Capella, Gabriel
Lynch综合征（LS）的分析算法越来越复杂。BRAF V600 E突变和MLH 1启动子高甲基化已被提议作为鉴别LS的筛选工具。本研究的目的是评估两种体细胞改变的临床实用性和成本效益，以提高LS诊断算法的产率。研究了122例来自有结直肠癌家族史的结直肠肿瘤，这些肿瘤显示微卫星不稳定性和/或错配修复（MMR）蛋白表达缺失。MMR种系突变57例（MLH 1 40例，MSH 2 15例，MSH 6 2例）。通过单核苷酸引物延伸评估BRAF V600 E突变。在71例MLH 1蛋白缺失的亚组中，通过甲基化特异性多重连接依赖性探针扩增评估MLH 1启动子超甲基化。开发了一个决策模型来估计用于检测MLH 1突变携带者的替代病例发现方法的增量成本。进行了单向敏感性分析，以评估估计的稳健性。BRAF突变缺失对LS患者描述的敏感性为96%（23/24），特异性为28%（13/47）。MLH 1基因启动子甲基化对散发性肿瘤的特异性为66%（31/47），敏感性为96%（23/24）。与BRAF研究和German MLH 1突变研究相比，使用超甲基化分析检测的每个额外突变的成本较低。MLH 1的体细胞高甲基化是一种准确且具有成本效益的预筛选方法，用于在怀疑LS且MLH 1蛋白表达缺失时选择MLH 1生殖系分析的候选患者。European Journal of Human Genetics（2012）20，762-768; doi：10.1038/ejhg.2011.277; 2012年1月25日在线发表
The analytical algorithm of Lynch syndrome (LS) is increasingly complex. BRAF V600E mutation and MLH1 promoter hypermethylation have been proposed as a screening tool for the identification of LS. The aim of this study was to assess the clinical usefulness and cost-effectiveness of both somatic alterations to improve the yield of the diagnostic algorithm of LS. A total of 122 colorectal tumors from individuals with family history of colorectal cancer that showed microsatellite instability and/or loss of mismatch repair (MMR) protein expression were studied. MMR germline mutations were detected in 57 cases (40 MLH1, 15 MSH2 and 2 MSH6). BRAF V600E mutation was assessed by single-nucleotide primer extension. MLH1 promoter hypermethylation was assessed by methylation-specific multiplex ligation-dependent probe amplification in a subset of 71 cases with loss of MLH1 protein. A decision model was developed to estimate the incremental costs of alternative case-finding methods for detecting MLH1 mutation carriers. One-way sensitivity analysis was performed to assess robustness of estimations. Sensitivity of the absence of BRAF mutations for depiction of LS patients was 96% (23/24) and specificity was 28% (13/47). Specificity of MLH1 promoter hypermethylation for depiction of sporadic tumors was 66% (31/47) and sensitivity of 96% (23/24). The cost per additional mutation detected when using hypermethylation analysis was lower when compared with BRAF study and germinal MLH1 mutation study. Somatic hypermethylation of MLH1 is an accurate and cost-effective pre-screening method in the selection of patients that are candidates for MLH1 germline analysis when LS is suspected and MLH1 protein expression is absent. European Journal of Human Genetics (2012) 20, 762-768; doi: 10.1038/ejhg.2011.277; published online 25 January 2012