Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.
Department of Pathology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
Curr Oncol. 2021 Jan 15;28(1):509-522. doi: 10.3390/curroncol28010052.
Approximately 2-6% of endometrial cancers (ECs) are due to Lynch Syndrome (LS), a cancer predisposition syndrome caused by germline pathogenic variants (PVs) affecting the DNA mismatch repair (MMR) pathway. Increasingly, universal tissue-based screening of ECs has been proposed as an efficient and cost-effective way to identify families with LS, though few studies have been published on Canadian cohorts. The purpose of this study was to evaluate the feasibility and overall performance of a universal immunohistochemistry (IHC) screening program for women with EC within a single Canadian university hospital centre.
From 1 October 2015 to 31 December 2017, all newly diagnosed ECs (n = 261) at our centre were screened for MMR protein deficiency by IHC. MMR deficiency was noted in 69 tumours (26.4%), among which 53 had somatic MLH1 promoter hypermethylation and were considered "screen-negative". The remaining MMR-deficient cases (n = 16) were considered "screen-positive" and were referred for genetic counselling and testing. Germline PVs were identified in 12/16 (75%). One additional PV was identified in a screen-negative individual who was independently referred to the Genetics service. This corresponds to an overall LS frequency of 5.0% among unselected women with EC, and 6.4% among women diagnosed under age 70 years. Our algorithm detected MMR gene pathogenic variants in 4.6% and 6.2% of unselected individuals and individuals under age 70 years, respectively. Four germline PVs (30.8%) were identified in individuals who did not meet any traditional LS screening criteria.
Universal IHC screening for women with EC is an effective and feasible method of identifying individuals with LS in a Canadian context.
约 2-6%的子宫内膜癌（EC）是由林奇综合征（LS）引起的，LS 是一种由影响 DNA 错配修复（MMR）途径的种系致病性变异（PV）引起的癌症易感性综合征。越来越多的研究提出对 EC 进行普遍的基于组织的筛查，以识别 LS 家族，但发表在加拿大队列上的研究较少。本研究旨在评估在加拿大的单一大学医院中心对 EC 患者进行普遍免疫组化（IHC）筛查计划的可行性和总体性能。
从 2015 年 10 月 1 日至 2017 年 12 月 31 日，对我们中心的所有新诊断的 EC（n=261）进行了 MMR 蛋白缺陷的 IHC 筛查。在 69 个肿瘤（26.4%）中观察到 MMR 缺陷，其中 53 个肿瘤存在体细胞 MLH1 启动子超甲基化，被认为是“筛查阴性”。其余的 MMR 缺陷病例（n=16）被认为是“筛查阳性”，并被转介进行遗传咨询和检测。在 16 例中确定了 12 例种系 PV（75%）。在一个独立转介到遗传服务的筛查阴性个体中发现了另一个 PV。这对应于未选择的 EC 女性中 LS 发生率为 5.0%，年龄小于 70 岁的女性中 LS 发生率为 6.4%。我们的算法在未选择的个体和年龄小于 70 岁的个体中分别检测到 MMR 基因致病性变异的发生率为 4.6%和 6.2%。在不符合任何传统 LS 筛查标准的个体中，确定了 4 个种系 PV（30.8%）。
对 EC 患者进行普遍的 IHC 筛查是一种在加拿大环境中识别 LS 患者的有效且可行的方法。
