The Cancer Genome Atlas Research Network conducted an integrated genomic, transcriptomic, and proteomic analysis of 373 endometrial carcinomas, revealing four distinct subtypes: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. Endometrioid tumors were classified based on mutations in genes like PTEN, CTNNB1, PIK3CA, ARID1A, and KRAS, while serous tumors showed frequent TP53 mutations and extensive copy number alterations. POLE mutations were associated with high mutation rates and improved survival, while copy-number high tumors had poor outcomes. The study identified molecular subtypes that could influence treatment decisions, such as chemotherapy for copy-number altered endometrioid tumors instead of radiotherapy. Endometrial cancers were found to have high mutation rates in the PI(3)K/AKT pathway, with distinct molecular features compared to other cancers. The findings suggest that genomic classification could improve treatment strategies for endometrial cancers, particularly for aggressive tumors. The study also highlighted the importance of molecular profiling in distinguishing between endometrioid and serous tumors, which may have different therapeutic responses. The research underscores the need for personalized treatment approaches based on molecular subtypes.The Cancer Genome Atlas Research Network conducted an integrated genomic, transcriptomic, and proteomic analysis of 373 endometrial carcinomas, revealing four distinct subtypes: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. Endometrioid tumors were classified based on mutations in genes like PTEN, CTNNB1, PIK3CA, ARID1A, and KRAS, while serous tumors showed frequent TP53 mutations and extensive copy number alterations. POLE mutations were associated with high mutation rates and improved survival, while copy-number high tumors had poor outcomes. The study identified molecular subtypes that could influence treatment decisions, such as chemotherapy for copy-number altered endometrioid tumors instead of radiotherapy. Endometrial cancers were found to have high mutation rates in the PI(3)K/AKT pathway, with distinct molecular features compared to other cancers. The findings suggest that genomic classification could improve treatment strategies for endometrial cancers, particularly for aggressive tumors. The study also highlighted the importance of molecular profiling in distinguishing between endometrioid and serous tumors, which may have different therapeutic responses. The research underscores the need for personalized treatment approaches based on molecular subtypes.