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

Abstract

A series of 42 patient tumors diagnosed as endometrial stromal sarcoma (ESS) based on the morphology but negative for <i>JAZF1</i> and/or <i>YWHAE</i> rearrangement 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 a <i>JAZF1-SUZ12</i> fusion, one high grade ESS harboring a <i>BCOR</i>-ITD, two uterine tumors resembling ovarian sex cord tumors, two samples each of uterine leiomyoma and leiomyosarcomas and a series of <i>BCOR</i>-rearranged family of tumor (<i>n</i> = 8) indicated that tumors could be gather in three distinct subgroups: one mainly composed of <i>BCOR</i>-rearranged samples that contained seven ESS samples, one mainly composed of <i>JAZF1</i>-fused ESS (<i>n</i> = 15) and the last composed of various molecular subtypes (<i>n</i> = 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, <i>p</i> = 0.004). While <i>YWHAE-NUTM2</i> fusion genes may be present in both high and low grade ESS, the high-grade presents with additional <i>BCOR</i> or <i>BCORL1</i> gene mutations. RNAseq brings clinically relevant molecular classification, enabling the reclassification of diseases and the guidance of therapeutic strategy.