EMMA-STRAT: a multi-omics based machine learning framework for stratification of endometrial carcinoma molecular subtypes and MSI status

Abstract Background Uterine Corpus Endometrial Carcinoma (UCEC) is the most common gynecologic malignancy, with molecular heterogeneity influencing prognosis and treatment response. Although TCGA-defined molecular subtypes and multi-omics datasets have improved biological understanding of UCEC, externally evaluated computational frameworks for molecular stratification remain limited. To address this, we developed EMMA-STRAT, a supervised multi-omics machine learning framework integrating mRNA expression, miRNA expression, and DNA methylation data to classify UCEC genomic subtypes and microsatellite instability (MSI) status. Results Using the TCGA cohort ( N = 433) for model development and internal validation, we benchmarked six classifiers and evaluated final model performance on two independent Clinical Proteomic Tumor Analysis Consortium (CPTAC) cohorts ( N = 95 and N = 108). Multi-omics integration consistently outperformed single-omics models, with RNA expression as the strongest standalone modality. For MSI-H versus MSS classification, a LightGBM model trained on 20 SVM-selected features per omics layer achieved an internal balanced accuracy of 98.1% and external balanced accuracies of 93.1–94.9%. For four-class genomic subtyping, a Multi-Layer Perceptron trained on 50 LASSO-selected features per omics layer achieved an internal balanced accuracy of 89.1% and external balanced accuracies of 84.7–86.2%. Both models showed favorable discrimination and probability calibration relative to reference baselines, although calibration estimates for low-prevalence classes including POLE should be interpreted cautiously. SHapley Additive exPlanations (SHAP)-based interpretability analysis identified model-selected features including MLH1 , CDKN2A , PPP4R4 , and hsa-miR-378a , with downstream analyses supporting their biological plausibility. All results are openly accessible via an interactive browser at https://naisarg14.github.io/EMMA-STRAT-web-viewer/index.html . Conclusions EMMA-STRAT provides an externally evaluated, research-grade computational framework for multi-omics molecular stratification of endometrial carcinoma. Integration of mRNA, miRNA, and DNA methylation data supported prediction of MSI-H versus MSS status and TCGA-defined genomic subtypes across independent cohorts. However, since EMMA-STRAT requires multi-omics data and was not directly compared with established clinical classifiers, it should currently be interpreted as a research-oriented molecular stratification framework rather than a clinically deployable decision-making model. The developed framework provides a basis for future prospective validation, incorporation of clinicopathological variables, and direct comparison with ProMisE-based or integrated clinical risk models.