Universal endometrial cancer tumor typing: How much has immunohistochemistry, microsatellite instability, and MLH1 methylation improved the diagnosis of Lynch syndrome across the population?
Universal endometrial cancer tumor typing: How much has immunohistochemistry, microsatellite instability, and MLH1 methylation improved the diagnosis of Lynch syndrome across the population?
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DOI：
10.1002/cncr.32203
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发表时间：
2019-09-15
期刊：
影响因子：
6.2
通讯作者：
Frey, Melissa K.
中科院分区：
文献类型：
--
作者：
Kahn, Ryan M.;Gordhandas, Sushmita;Frey, Melissa K.
背景对于所有被诊断为子宫内膜癌的女性，建议对缺陷DNA错配修复(MMR)进行通用肿瘤检测，以确定那些潜在的Lynch综合征患者。然而，这些筛查方法在整个人群中识别林奇综合征患者的有效性还没有得到很好的研究。本研究的目的是评估MMR免疫组织化学(IHC)、突变L同源基因1(MLH1)甲基化和微卫星不稳定性(MSI)分析在子宫内膜癌患者中的结果。方法对1990-2018年的PubMed、EMBASE、MEDLINE、Cochrane图书馆等数据库进行系统检索。采用德西蒙尼-莱尔德随机效应模型Meta分析估计Lynch综合征诊断的加权患病率。结果综合检索共产生4400篇文献。29项同行评议的研究符合纳入标准。对6649例子宫内膜癌患者进行全科肿瘤分子筛查，经胚系基因检测确诊为Lynch综合征206例(3%)。在5917例接受肿瘤免疫组化检查的患者中，28%的患者染色异常。在接受MSI分析的3140名患者中，31%的患者出现了MSI。在子宫内膜癌患者中，IHC染色缺失的Lynch综合征胚系突变加权患病率为15%(95%可信区间，11%~18%)，MSI分析阳性者为19%(95%CI，13%~26%)。在MLH1表达缺失的1159例患者中，接受甲基化检测的患者中有143例(13.7%)为MLH1甲基化阴性，32例显示有胚系MLH1突变(占所有MLH1缺失病例的2.8%和所有MLH1甲基化阴性病例的22.4%)。在通过肿瘤分型被诊断为林奇综合征的子宫内膜癌患者中，仅通过基于家族病史的筛查就会错过43%。结论：尽管在子宫内膜癌中普遍实施了肿瘤检测，但有关检测结果的数据仍然有限。这项研究提供了预测值，将帮助从业者评估林奇综合征背景下的异常结果，并帮助他们进行患者咨询。
Background Universal tumor testing for defective DNA mismatch repair (MMR) is recommended for all women diagnosed with endometrial cancer to identify those with underlying Lynch syndrome. However, the effectiveness of these screening methods in identifying individuals with Lynch syndrome across the population has not been well studied. The aim of this study was to evaluate outcomes of MMR immunohistochemistry (IHC), mutL homolog 1 (MLH1) methylation, and microsatellite instability (MSI) analysis among patients with endometrial cancer. Methods A complete systematic search of online databases (PubMed, EMBASE, MEDLINE, and the Cochrane Library) for 1990-2018 was performed. A DerSimonian-Laird random effects model meta-analysis was used to estimate the weighted prevalence of Lynch syndrome diagnoses. Results The comprehensive search produced 4400 publications. Twenty-nine peer-reviewed studies met the inclusion criteria. Patients with endometrial cancer (n = 6649) were identified, and 206 (3%) were confirmed to have Lynch syndrome through germline genetic testing after positive universal tumor molecular screening. Among 5917 patients who underwent tumor IHC, 28% had abnormal staining. Among 3140 patients who underwent MSI analysis, 31% had MSI. Among patients with endometrial cancer, the weighted prevalence of Lynch syndrome germline mutations was 15% (95% confidence interval [CI], 11%-18%) with deficient IHC staining and 19% (95% CI, 13%-26%) with a positive MSI analysis. Among 1159 patients who exhibited a loss of MLH1 staining, 143 (13.7%) were found to be MLH1 methylation-negative among those who underwent methylation testing, and 32 demonstrated a germline MLH1 mutation (2.8% of all absent MLH1 staining cases and 22.4% of all MLH1 methylation-negative cases). Forty-three percent of patients with endometrial cancer who were diagnosed with Lynch syndrome via tumor typing would have been missed by family history-based screening alone. Conclusions Despite the widespread implementation of universal tumor testing in endometrial cancer, data regarding testing results remain limited. This study provides predictive values that will help practitioners to evaluate abnormal results in the context of Lynch syndrome and aid them in patient counseling.