为了识别MLH1高甲基化与MLH1突变（“林奇样”）子宫内膜癌之间的不同生存结果和免疫检查点抑制剂（ICI）的反应，并确定它们的分子特征是否能解释不同的结果，分析了1673例错配修复缺陷的子宫内膜癌（由Caris Life Sciences，凤凰城，亚利桑那进行的下一代测序和全转录组测序）。通过免疫组化法检测PD-L1，ER和PR，并使用MCP-counter计算免疫细胞浸润。使用卡方检验和Mann-Whitney U检验进行显著性分析，并进行多重比较的调整。使用Kaplan-Meier生存曲线描述总体生存率（OS）。子宫内膜癌队列包括89.2％具有MLH1高甲基化肿瘤的患者和10.8％具有MLH1突变肿瘤的患者，两组的中位年龄分别为67和60岁（p < 0.01）。MLH1高甲基化肿瘤患者的总体生存率显著较差，并且在ICI治疗后的总体生存率趋于较差，相比之下，MLH1突变肿瘤患者的情况较好。MLH1高甲基化相对于MLH1突变的免疫微环境表现为PD-L1阳性率、免疫检查点基因表达、免疫细胞浸润、T细胞浸润评分和干扰素γ（IFNγ）评分的降低。MLH1高甲基化还与TP53和DNA损伤修复基因的突变率降低以及JAK1、FGFR2、CCND1和PTEN基因突变率的增加以及ER和PR阳性率的增加相关。MLH1高甲基化的子宫内膜癌患者显示出明显降低的生存率和与MLH1突变肿瘤相比不一致的免疫治疗反应，这与不同的突变谱、更冷的免疫表型以及MLH1高甲基化肿瘤中ER/PR表达的增加有关。提供者可以考虑将单剂ICI转为多剂方案或激素治疗来治疗MLH1高甲基化肿瘤的患者。 版权所有 © 2023 Elsevier Inc. 保留所有权利。

To identify differential survival outcomes and immune checkpoint inhibitor (ICI) response in MLH1 hypermethylated versus MLH1 mutated ("Lynch-like") endometrial tumors and determine whether their molecular profiles can elucidate the differential outcomes.1673 mismatch repair deficient endometrial tumors were analyzed by next-generation sequencing and whole transcriptome sequencing (Caris Life Sciences, Phoenix, AZ). PD-L1, ER, and PR were tested by immunohistochemistry and immune cell infiltrates were calculated using MCP-counter. Significance was determined using Chi-square and Mann-Whitney U tests and adjusted for multiple comparisons. Overall survival (OS) was depicted using Kaplan-Meier survival curves.The endometrial cancer cohort comprised 89.2% patients with MLH1 hypermethylated tumors and 10.8% with MLH1 mutated tumors, with median ages of 67 and 60 years, respectively (p < 0.01). Patients with MLH1 hypermethylated tumors had significantly worse OS and trended toward worse OS following ICI treatment than patients with MLH1 mutated tumors. The immune microenvironment of MLH1 hypermethylated relative to MLH1 mutated was characterized by decreased PD-L1 positivity, immune checkpoint gene expression, immune cell infiltration, T cell inflamed scores, and interferon gamma (IFNγ) scores. MLH1 hypermethylation was also associated with decreased mutation rates in TP53 and DNA damage repair genes, but increased rates of JAK1, FGFR2, CCND1, and PTEN mutations, as well as increased ER and PR positivity.Endometrial cancer patients with MLH1 hypermethylation display significantly decreased survival and discrepant immunotherapy responses compared to patients with MLH1 mutated tumors, which was associated with differential mutational profiles, a more immune cold phenotype, and increased ER/PR expression in MLH1 hypermethylated tumors. Providers may consider early transition from single agent ICI to a multi-agent regimen or hormonal therapy for patients with MLH1 hypermethylated tumors.Copyright © 2023 Elsevier Inc. All rights reserved.