Molecular Classification of Endometrial Stromal Sarcomas Using RNA Sequencing Defines Nosological and Prognostic Subgroups with Different Natural History

Simple Summary In about half of the cases, endometrial stromal sarcomas lack the canonical oncogenic fusionsJAZF1-SUZ12orYWHAE-NUTM2, which are mutually exclusive. The aim of this study was to explore by RNA sequencing a retrospective series of uterine sarcomas diagnosed as endometrial stromal sarcomas but negative forJAZF1and/orYWHAErearrangement in FISH, in order to provide a better description of their molecular landscape, improve the classification of endometrial stromal sarcomas and provide guidance for disease management. A series of 42 patient tumors diagnosed as endometrial stromal sarcoma (ESS) based on the morphology but negative forJAZF1and/orYWHAErearrangement in FISH was analyzed by RNA-sequencing. A chromosomal rearrangement was identified in 31 (74%) of the cases and a missense mutation in known oncogenes/tumor suppressor genes in 11 (26%). Cluster analyses on the expression profiles from this series together with a control cohort composed of five samples of low grade ESS harboring aJAZF1-SUZ12fusion, one high grade ESS harboring aBCOR-ITD, two uterine tumors resembling ovarian sex cord tumors, two samples each of uterine leiomyoma and leiomyosarcomas and a series ofBCOR-rearranged family of tumor (n= 8) indicated that tumors could be gather in three distinct subgroups: one mainly composed ofBCOR-rearranged samples that contained seven ESS samples, one mainly composed ofJAZF1-fused ESS (n= 15) and the last composed of various molecular subtypes (n= 19). These three subgroups display different gene signatures, different in silico cell cycle scores and very different clinical presentations, natural history and survival (log-rank test,p= 0.004). WhileYWHAE-NUTM2fusion genes may be present in both high and low grade ESS, the high-grade presents with additionalBCORorBCORL1gene mutations. RNAseq brings clinically relevant molecular classification, enabling the reclassification of diseases and the guidance of therapeutic strategy.