Pasanen Annukka, Loukovaara Mikko, Kaikkonen Elina, Olkinuora Alisa, Pylvänäinen Kirsi, Alhopuro Pia, Peltomäki Päivi, Mecklin Jukka-Pekka, Bützow Ralf
Department of Pathology, Helsinki University Hospital, University of Helsinki, 00290 Helsinki, Finland.
Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, 00290 Helsinki, Finland.
Cancers (Basel). 2022 Mar 6;14(5):1348. doi: 10.3390/cancers14051348.
International guidelines recommend universal screening of endometrial carcinoma (EC) patients for Lynch syndrome (LS). This screening is generally based on mismatch repair (MMR) protein immunohistochemistry followed by methylation analysis of MLH1-negative cases to exclude the likely sporadic cases from germline testing. As LS-associated EC is uncommon in the elderly, age-selective methylation testing could improve cost-efficiency. We performed MMR immunohistochemistry on 821 unselected ECs (clinic-based cohort) followed by a promoter methylation test of all MLH1/PMS2-negative tumors. Non-methylated MLH1-deficient cases underwent NGS and MLPA-based germline analyses to identify mutation carriers. A reduction in the test burden and corresponding false negative rates for LS screening were investigated for various age cut-offs. In addition, the age distribution of 132 mutation carriers diagnosed with EC (registry-based cohort) was examined. A germline mutation was found in 2/14 patients with non-methylated MLH1-deficient EC. When compared to a universal methylation analysis, selective testing with a cut-off age of 65 years, would have reduced the testing effort by 70.7% with a false negative rate for LS detection of 0% and 3% in the clinic and registry-based cohorts, respectively. The use of age-selective methylation analysis is a feasible way of reducing the costs and laboratory burden in LS screening for EC patients.
国际指南建议对子宫内膜癌（EC）患者进行林奇综合征（LS）的普遍筛查。这种筛查通常基于错配修复（MMR）蛋白免疫组化，随后对MLH1阴性病例进行甲基化分析，以将可能的散发性病例排除在种系检测之外。由于与LS相关的EC在老年人中并不常见，年龄选择性甲基化检测可以提高成本效益。我们对821例未经选择的EC（基于临床的队列）进行了MMR免疫组化，随后对所有MLH1/PMS2阴性肿瘤进行了启动子甲基化检测。非甲基化的MLH1缺陷病例接受了基于二代测序（NGS）和多重连接探针扩增（MLPA）的种系分析，以识别突变携带者。我们研究了不同年龄界限下LS筛查的检测负担降低情况以及相应的假阴性率。此外，我们还检查了132例诊断为EC的突变携带者（基于登记的队列）的年龄分布。在2/14例非甲基化MLH1缺陷的EC患者中发现了种系突变。与普遍甲基化分析相比，采用65岁的年龄界限进行选择性检测，在基于临床和登记的队列中，分别可将检测工作量减少70.7%，LS检测的假阴性率分别为0%和3%。使用年龄选择性甲基化分析是降低EC患者LS筛查成本和实验室负担的一种可行方法。
