The Cancer Genome Atlas Research Network conducted an integrated genomic, transcriptomic, and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. The study identified four distinct categories of endometrial cancers based on genomic features: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas shared genomic features with ovarian serous and basal-like breast carcinomas. The findings suggest that genomic-based classification may improve the management of aggressive endometrial cancers, potentially affecting post-surgical adjuvant treatment decisions. The study also highlighted the importance of reclassifying histologically misclassified cases and the need for separate clinical trials for endometrioid and serous-like tumors to develop effective treatment paradigms.The Cancer Genome Atlas Research Network conducted an integrated genomic, transcriptomic, and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. The study identified four distinct categories of endometrial cancers based on genomic features: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas shared genomic features with ovarian serous and basal-like breast carcinomas. The findings suggest that genomic-based classification may improve the management of aggressive endometrial cancers, potentially affecting post-surgical adjuvant treatment decisions. The study also highlighted the importance of reclassifying histologically misclassified cases and the need for separate clinical trials for endometrioid and serous-like tumors to develop effective treatment paradigms.