Division of Gynecologic Oncology, Princess Margaret Cancer Centre, University Health Network, Sinai Health Systems, Toronto, Ontario, Canada.
Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, Canada.
Cancer. 2020 Nov 15;126(22):4886-4894. doi: 10.1002/cncr.33144. Epub 2020 Aug 18.
For women with ovarian cancer (OC), the optimal screening strategy to identify Lynch syndrome (LS) has not been determined. In the current study, the authors compared the performance characteristics of various strategies combining mismatch repair (MMR) immunohistochemistry (IHC), microsatellite instability testing (MSI), and family history for the detection of LS.
Women with nonserous and/or nonmucinous ovarian cancer were recruited prospectively from 3 cancer centers in Ontario, Canada. All underwent germline testing for LS and completed a family history assessment. Tumors were assessed using MMR IHC and MSI. The sensitivity, specificity, and positive and negative predictive values of screening strategies were compared with the gold standard of a germline result.
Of 215 women, germline data were available for 189 (88%); 13 women (7%) had pathogenic germline variants with 7 women with mutS homolog 6 (MSH6); 3 women with mutL homolog 1 (MLH1); 2 women with PMS1 homolog 2, mismatch repair system component (PMS2); and 1 woman with mutS homolog 2 (MSH2). A total of 28 women had MMR-deficient tumors (13%); of these, 11 had pathogenic variants (39%). Sequential IHC (with MLH1 promoter methylation analysis on MLH1-deficient tumors) followed by MSI for nonmethylated and/or MMR-intact patients was the most sensitive (92.3%; 95% confidence interval, 64%-99.8%) and specific (97.7%; 95% confidence interval, 94.2%-99.4%) approach, missing 1 case of LS. IHC with MLH1 promoter methylation analysis missed 2 patients of LS. Family history was found to have the lowest sensitivity at 55%.
Sequential IHC (with MLH1 promoter methylation analysis) followed by MSI was found to be most sensitive. However, IHC with MLH1 promoter methylation analysis also performed well and is likely more cost-effective and efficient in the clinical setting. The pretest probability of LS is high in patients with MMR deficiency and warrants universal screening for LS.
对于卵巢癌（OC）女性患者，确定最佳的林奇综合征（LS）筛查策略尚未明确。在本研究中，作者比较了结合错配修复（MMR）免疫组化（IHC）、微卫星不稳定性检测（MSI）和家族史的各种策略来检测 LS 的性能特征。
前瞻性地从加拿大安大略省的 3 家癌症中心招募非浆液性和/或非黏液性卵巢癌女性患者。所有患者均接受 LS 的种系检测，并完成家族史评估。使用 MMR IHC 和 MSI 评估肿瘤。比较了筛查策略的敏感性、特异性、阳性预测值和阴性预测值与种系结果的金标准。
在 215 名女性中，有 189 名（88%）的女性有可供分析的种系数据；13 名女性（7%）携带致病性种系变异，其中 7 名女性为 mutS 同源物 6（MSH6）；3 名女性为 mutL 同源物 1（MLH1）；2 名女性为 PMS1 同源物 2，错配修复系统成分（PMS2）；1 名女性为 mutS 同源物 2（MSH2）。共有 28 名女性的肿瘤存在 MMR 缺陷（13%），其中 11 名女性携带致病性变异（39%）。对于 MMR 缺陷肿瘤，先进行免疫组化（对 MMR 缺陷肿瘤进行 MLH1 启动子甲基化分析），然后对非甲基化和/或 MMR 完整的患者进行 MSI 检测，是最敏感（92.3%；95%置信区间，64%-99.8%）和特异（97.7%；95%置信区间，94.2%-99.4%）的方法，漏诊了 1 例 LS 患者。免疫组化联合 MLH1 启动子甲基化分析漏诊了 2 例 LS 患者。家族史的敏感性最低，为 55%。
先进行免疫组化（对 MMR 缺陷肿瘤进行 MLH1 启动子甲基化分析），然后进行 MSI 检测，结果最敏感。然而，免疫组化联合 MLH1 启动子甲基化分析也表现良好，并且在临床环境中可能更具成本效益和效率。在 MMR 缺陷的患者中，LS 的先验概率较高，需要对 LS 进行普遍筛查。
