Purpose: Microsatellite instability–high (MSI-H) endometrial carcinomas are underpinned by distinct mechanisms of DNA mismatch repair deficiency (MMR-D). We sought to characterize the clinical and genetic features of MSI-H endometrial cancers harboring germline or somatic mutations in MMR genes or MLH1 promoter hypermethylation (MLH1ph). Experimental Design: Of > 1,100 patients with endometrial cancer that underwent clinical tumor-normal sequencing, 184 had MSI-H endometrial cancers due to somatic MMR mutations or MLH1ph, or harbored pathogenic germline MMR mutations. Clinicopathologic features, mutational landscape, and tumor-infiltrating lymphocyte (TIL) scores were compared among MMR-D groups using nonparametric tests. Log-rank tests were used for categorical associations; Kaplan–Meier method and Wald test based on Cox proportional hazards models were employed for continuous variables and survival analyses. Results: Compared with patients with germline (n = 25) and somatic (n = 39) mutations, patients with MLH1ph endometrial cancers (n = 120) were older (P < 0.001), more obese (P = 0.001) and had more advanced disease at diagnosis (P = 0.025). MLH1ph endometrial cancers were enriched for JAK1 somatic mutations as opposed to germline MMR-D endometrial cancers which showed enrichment for pathogenic ERBB2 mutations. MLH1ph endometrial cancers exhibited lower tumor mutational burden and TIL scores compared with endometrial cancers harboring germline or somatic MMR mutations (P < 0.01). MLH1ph endometrial cancer patients had shorter progression-free survival (PFS) on univariate analysis, but in multivariable models, stage at diagnosis remained the only predictor of survival. For stage I/II endometrial cancer, two-year PFS was inferior for patients with MLH1ph endometrial cancers compared with germline and somatic MMR groups (70% vs. 100%, respectively). Conclusions: MLH1ph endometrial cancers likely constitute a distinct clinicopathologic entity compared with germline and somatic MMR-D ECs with potential treatment implications.

中文翻译：

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微卫星不稳定性——MLH1启动子高甲基化的高子宫内膜癌具有独特的分子和临床特征

目的：高微卫星不稳定性 (MSI-H) 子宫内膜癌的基础是 DNA 错配修复缺陷 (MMR-D) 的独特机制。我们试图描述具有 MMR 基因种系或体细胞突变或 MLH1 启动子高甲基化 (MLH1ph) 的 MSI-H 子宫内膜癌的临床和遗传特征。实验设计：> 1,100 名子宫内膜癌患者接受了临床肿瘤正常测序，其中 184 名患者因体细胞 MMR 突变或 MLH1ph 或携带致病性种系 MMR 突变而患有 MSI-H 子宫内膜癌。使用非参数检验比较 MMR-D 组之间的临床病理特征、突变情况和肿瘤浸润淋巴细胞 (TIL) 评分。对数秩检验用于分类关联；采用 Kaplan-Meier 方法和基于 Cox 比例风险模型的 Wald 检验进行连续变量和生存分析。结果：与生殖系突变 (n = 25) 和体细胞突变 (n = 39) 的患者相比，MLH1ph 子宫内膜癌患者 (n = 120) 年龄更大 (P < 0.001)、肥胖程度更高 (P = 0.001)，且诊断时疾病已处于晚期（P = 0.025）。MLH1ph 子宫内膜癌富含 JAK1 体细胞突变，而种系 MMR-D 子宫内膜癌则富含致病性 ERBB2 突变。与携带种系或体细胞 MMR 突变的子宫内膜癌相比，MLH1ph 子宫内膜癌表现出较低的肿瘤突变负荷和 TIL 评分（P < 0.01）。在单变量分析中，MLH1ph 子宫内膜癌患者的无进展生存期 (PFS) 较短，但在多变量模型中，诊断时的分期仍然是生存的唯一预测因素。对于 I/II 期子宫内膜癌，与种系和体细胞 MMR 组相比，MLH1ph 子宫内膜癌患者的两年 PFS 较差（分别为 70% 和 100%）。结论：与种系和体细胞 MMR-D EC 相比，MLH1ph 子宫内膜癌可能构成独特的临床病理实体，具有潜在的治疗意义。