Hereditary Cancer Progam, Institut Català d'Oncologia, IDIBELL, Hospitalet de Llobregat, Spain.
Eur J Hum Genet. 2012 Jul;20(7):762-8. doi: 10.1038/ejhg.2011.277. Epub 2012 Jan 25.
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.
林奇综合征（LS）的分析算法越来越复杂。BRAF V600E 突变和 MLH1 启动子甲基化已被提议作为识别 LS 的筛选工具。本研究旨在评估这两种体细胞改变对提高 LS 诊断算法的产量的临床有用性和成本效益。共研究了 122 例来自有结直肠癌家族史的个体的结直肠肿瘤，这些肿瘤表现出微卫星不稳定性和/或错配修复（MMR）蛋白表达缺失。在 57 例（40 例 MLH1、15 例 MSH2 和 2 例 MSH6）中检测到 MMR 种系突变。通过单核苷酸引物延伸评估 BRAF V600E 突变。在 71 例 MLH1 蛋白缺失的病例中，通过甲基化特异性多重连接依赖性探针扩增评估 MLH1 启动子甲基化。建立了一个决策模型来估计替代病例发现方法检测 MLH1 突变携带者的增量成本。进行了单因素敏感性分析以评估估计的稳健性。缺乏 BRAF 突变对描绘 LS 患者的敏感性为 96%（23/24），特异性为 28%（13/47）。MLH1 启动子甲基化对描绘散发性肿瘤的特异性为 66%（31/47），敏感性为 96%（23/24）。与 BRAF 研究和种系 MLH1 突变研究相比，使用甲基化分析检测额外突变的成本更低。当怀疑 LS 且 MLH1 蛋白表达缺失时，MLH1 的体细胞甲基化是一种准确且具有成本效益的预筛选方法，可选择 MLH1 种系分析的候选患者。
