Microsatellite instability-high (MSI-H) endometrial carcinomas are underpinned by distinct mechanisms of DNA mismatch repair deficiency (MMR-D). Researchers aimed to describe the clinical and genetic characteristics of MSI-H endometrial malignancies with hypermethylation (MLH1) promoter or germline or somatic mutations in MMR genes. Of more than 1,100 individuals with endometrial cancer who received clinical tumor-normal sequencing, 18% of these had MSI-H endometrial tumors caused by somatic MMR mutations or MLH1ph or had pathogenic germline MMR mutations. Investigators used nonparametric tests to assess clinicopathologic characteristics, mutational landscape, and tumor-infiltrating lymphocyte (TIL) ratings between MMR-D groups. Categorical associations were evaluated using log-rank tests, while continuous variables and survival analyses were analyzed using the Kaplan-Meier method and the Wald test based on Cox proportional hazards models. Patients with MLH1ph endometrial malignancies (n=120) were older (P<0.001), more obese (P=0.001), and had more advanced disease at diagnosis (P=0.025) than patients with germline (n=25) and somatic (n = 39) mutations. In contrast to germline MMR-D endometrial cancers, which showed enrichment for harmful ERBB2 mutations, MLH1ph endometrial tumors were enriched for JAK1 somatic mutations. In addition, tumor mutational load and TIL scores were lower in MLH1ph endometrial tumors compared to endometrial cancers with germline or somatic MMR mutations (P<0.01). On univariate analysis, patients with MLH1ph endometrial cancer had shorter PFS, but in multivariate models, the stage at diagnosis was the only predictor of survival. Compared to germline and somatic MMR groups, individuals with stage I/II endometrial malignancies who lacked MLH1 had a lower 2-year progression-free survival (PFS). In comparison to germline and somatic MMR-D ECs, MLH1ph ECs are expected to comprise a separate clinicopathologic entity with possible treatment implications. 

Source: aacrjournals.org/clincancerres/article/28/19/4302/709311/Microsatellite-Instability-High-Endometrial