Genomic subtypes and cellular phenotypes of high-grade endometrial carcinoma

Abstract

Recent genomic analyses of endometrial carcinoma (EC) have delineated four distinct subtypes: ultra-mutated (POLE) type, microsatellite instability–high (MSI-H) type, copy number–high (CN-H) type, and copy number–low (CN-L) type. Despite these classifications, the relationship between genomic subtype and histological classification of high-grade EC remains obscure. This study is a comprehensive genomic analysis specifically focusing on high-grade EC. Examination of 81 high-grade EC tumors revealed that serous carcinoma is frequently characterized by TP53 mutations as described previously. However, the correspondence between genomic subtype and histological classification of high-grade EC was weak overall. Gene expression–based clustering showed that clear cell carcinoma, not specifically associated with any particular genomic subtype, had high expression of glandular/lumenal cell marker genes. We also identified a subset of tumors characterized by the expression of genes related to ciliated cells. Our findings underscore the significance of considering cellular phenotypes that might reflect cell of origin and differentiation status, alongside genomic subtype, to precisely understand individual tumors of various histological types. Importantly, cellular phenotype might be closely associated with the immunological status of cancer cells; tumors with the glandular/lumenal phenotype are thought to present antigens more efficiently. Such stratification might have clinical implications, potentially impacting post-surgical adjuvant treatment or the use of immune therapy in women with high-grade EC. We propose that RNA clustering is a clinically valuable tool for the precise stratification and treatment planning for high-grade EC, emphasizing its potential to enhance personalized medicine approaches for EC.