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Microsatellite instability-high endometrial cancers with MLH1 promoter hypermethylation have distinct molecular and clinical profiles.

PURPOSE
Microsatellite instability-high (MSI-H) endometrial carcinomas (ECs) are underpinned by distinct mechanisms of DNA mismatch repair deficiencies (MMR-D). We sought to characterize clinical and genetic features of MSI-H ECs harboring germline or somatic mutations in MMR genes or MLH1 promoter hypermethylation (MLH1ph).


DESIGN
Of >1,100 EC patients that underwent clinical tumor-normal sequencing, 184 displayed MSI-H ECs 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 non-parametric 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 to patients with germline (n=25) and somatic (n=39) mutations, patients with MLH1ph ECs (n=120) were older (p<0.001), more obese (p=0.001) and had more advanced disease at diagnosis (p=0.025). MLH1ph ECs were enriched for JAK1 somatic mutations as opposed to germline MMR-D ECs which showed enrichment for pathogenic ERBB2 mutations. MLH1ph ECs exhibited lower tumor mutational burden and TIL scores compared to ECs harboring germline or somatic MMR mutations (p<0.01). MLH1ph EC 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 EC, two-year PFS was inferior for patients with MLH1ph ECs compared to germline and somatic MMR groups (70% vs. 100%, respectively).


CONCLUSIONS
MLH1ph ECs likely constitute a distinct clinicopathologic entity compared to germline and somatic MMR-D ECs with potential treatment implications.