Background/Objectives:Mismatch repair (MMR) deficiency can be indicative of Lynch syndrome (LS) and guide treatment with immune checkpoint inhibitors. Colorectal cancers (CRCs) and endometrial cancers (ECs) are routinely screened to identify LS, primarily using immunohistochemistry (IHC) or microsatellite instability (MSI) testing, but concordance between these methods is variable in ECs. Here, we investigate this variability in 361 ECs from the Ohio OCCPI/OPTEC (n= 196) and Manchester PETALS (n= 165) trials, where concordance between assays differed significantly.Methods:Samples were re-tested using the amplicon-sequencing-based Newcastle MSI assay (NCL_MSI), and analysed with respect to existing IHC, MSI and MLH1 promoter hypermethylation data.Results:NCL_MSI showed consistency with the Ohio results (94% and 97% concordance with IHC and original MSI assays, respectively) and increased concordance within the Manchester cohort from 78% to 86% (MSI) and 84% (IHC). Among discordant Manchester samples, NCL_MSI was significantly associated withMLH1promoter methylation status (p= 0.0028) and had the highest concordance with methylation, (62/69 samples, 90%), indicating utility as a screening tool in this tumour type. However, tumours with germlineMSH6defects were only detected efficiently with IHC; seven out of eight LS tumours classified as MSS by either MSI assay had isolated MSH6 loss, compared to four out of twelve classified as MSI-H by both (p= 0.028). Furthermore, reduced MSI signal was observed in tumours with isolated MSH6 loss (p= 0.009 Ohio,p= 6.2 × 10−5Manchester) and in both ECs and CRCs with germline defects, although this only reached significance in CRCs (p= 0.002).Conclusions:These results provide further evidence that ECs with MSH6 loss in particular and LS tumours in general have an attenuated MSI signal, providing support for current guidelines specifically recommending IHC for LS detection and immune checkpoint therapy assessment in EC.
背景/目的：错配修复（MMR）缺陷可能提示林奇综合征（LS）并指导免疫检查点抑制剂治疗。结直肠癌（CRC）和子宫内膜癌（EC）通常通过免疫组化（IHC）或微卫星不稳定性（MSI）检测进行LS筛查，但两种方法在EC中的一致性存在差异。本研究基于俄亥俄州OCCPI/OPTEC试验（n=196）和曼彻斯特PETALS试验（n=165）的361例EC样本，探讨了检测方法间显著不一致的现象。 方法：使用基于扩增子测序的纽卡斯尔MSI检测（NCL_MSI）对样本进行复测，并结合现有IHC、MSI及MLH1启动子高甲基化数据进行分析。 结果：NCL_MSI与俄亥俄州队列结果高度一致（与IHC及原始MSI检测的一致性分别为94%和97%），并将曼彻斯特队列的一致性从78%提升至86%（MSI）和84%（IHC）。在曼彻斯特队列的不一致样本中，NCL_MSI与MLH1启动子甲基化状态显著相关（p=0.0028），且与甲基化检测的一致性最高（69例样本中62例一致，90%），表明其在该肿瘤类型中可作为有效的筛查工具。然而，胚系MSH6缺陷肿瘤仅通过IHC被有效检出：在两种MSI检测均判定为微卫星稳定（MSS）的8例LS肿瘤中，7例存在孤立性MSH6缺失；而在两种检测均判定为高度微卫星不稳定（MSI-H）的12例中仅4例存在此现象（p=0.028）。此外，在孤立性MSH6缺失的肿瘤中观察到MSI信号减弱（俄亥俄州队列p=0.009，曼彻斯特队列p=6.2×10−5），且在胚系缺陷的EC和CRC中均存在此趋势，但仅在CRC中达到统计学显著性（p=0.002）。 结论：本研究进一步证实，特别是存在MSH6缺失的EC及广义的LS肿瘤会呈现衰减的MSI信号，这为当前指南特别推荐使用IHC进行EC的LS筛查及免疫检查点治疗评估提供了支持依据。
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