Mendiola Marta, Heredia-Soto Victoria, Ruz-Caracuel Ignacio, Baillo Amparo, Ramon-Patino Jorge Luis, Escudero Francisco Javier, Miguel Maria, Pelaez-Garcia Alberto, Hernandez Alicia, Feliu Jaime, Hardisson David, Redondo Andres
Molecular Pathology and Therapeutic Targets Group, Hospital La Paz Institute for Health Research (IdiPAZ), 28046 Madrid, Spain.
Center for Biomedical Research in the Cancer Network (CIBERONC), Instituto de Salud Carlos III, 28029 Madrid, Spain.
Int J Mol Sci. 2023 Sep 23;24(19):14468. doi: 10.3390/ijms241914468.
Approximately 20-30% of endometrial carcinomas (EC) are characterized by mismatch repair (MMR) deficiency (dMMR) or microsatellite instability (MSI), and their testing has become part of the routine diagnosis. The aim of this study was to establish and compare the MMR status using various approaches. Immunohistochemistry (IHC), PCR-based MSI, and the detection of defects in the four key MMR genes (MLH1, PMS2, MSH2, and MSH6) via methylation-specific multiplex ligation-dependent probe amplification (MLPA) and targeted next-generation sequencing (NGS) were performed. MSH3 expression was also evaluated. A set of 126 early-stage EC samples were analyzed, 53.2% of which were dMMR and 46.8% of which were proficient MMR (pMMR) as determined using IHC, whereas 69.3% were classified as microsatellite stable, while 8.8% and 21.9% were classified MSI-low (MSI-L) and MSI-high (MSI-H), respectively. In total, 44.3% of the samples showed genetic or epigenetic alterations in one or more genes; MLH1 promoter methylation was the most common event. Although acceptable concordance was observed, there were overall discrepancies between the three testing approaches, mainly associated with the dMMR group. IHC had a better correlation with MMR genomic status than the MSI status determined using PCR. Further studies are needed to establish solid conclusions regarding the best MMR assessment technique for EC.
大约20%-30%的子宫内膜癌（EC）具有错配修复（MMR）缺陷（dMMR）或微卫星不稳定性（MSI）特征，对其进行检测已成为常规诊断的一部分。本研究的目的是使用各种方法建立并比较MMR状态。进行了免疫组织化学（IHC）、基于聚合酶链反应（PCR）的MSI检测，以及通过甲基化特异性多重连接依赖探针扩增（MLPA）和靶向新一代测序（NGS）检测四个关键MMR基因（MLH1、PMS2、MSH2和MSH6）的缺陷。还评估了MSH3的表达。分析了一组126例早期EC样本，其中53.2%为dMMR，46.8%为错配修复功能正常（pMMR），这是通过IHC确定的；而69.3%被分类为微卫星稳定，8.8%和21.9%分别被分类为低微卫星不稳定性（MSI-L）和高危卫星不稳定性（MSI-H）。总体而言，44.3%的样本在一个或多个基因中显示出遗传或表观遗传改变；MLH1启动子甲基化是最常见的事件。尽管观察到了可接受的一致性，但三种检测方法之间总体上存在差异，主要与dMMR组有关。与使用PCR确定的MSI状态相比，IHC与MMR基因组状态的相关性更好。需要进一步研究以确定关于EC最佳MMR评估技术的确切结论。
