Abstract
Simple SummaryIn about half of the cases, endometrial stromal sarcomas lack the canonical oncogenic fusions JAZF1-SUZ12 or YWHAE-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 for JAZF1 and/or YWHAE rearrangement 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 for JAZF1 and/or YWHAE 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 JAZF1-SUZ12 fusion, one high grade ESS harboring a BCOR-ITD, two uterine tumors resembling ovarian sex cord tumors, two samples each of uterine leiomyoma and leiomyosarcomas and a series of BCOR-rearranged family of tumor (n = 8) indicated that tumors could be gather in three distinct subgroups: one mainly composed of BCOR-rearranged samples that contained seven ESS samples, one mainly composed of JAZF1-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). While YWHAE-NUTM2 fusion genes may be present in both high and low grade ESS, the high-grade presents with additional BCOR or BCORL1 gene mutations. RNAseq brings clinically relevant molecular classification, enabling the reclassification of diseases and the guidance of therapeutic strategy.
Highlights
Endometrial stromal sarcoma (ESS) is a rare disease accounting for less than 1% of all uterine tumors [1]
The HG group is composed of endometrial stromal sarcoma (ESS) harboring a BCOR rearrangement, while the LG group is composed of ESS that harbors a fusion of a PRC2 zinc finger protein (e.g., JAZF1, PHF1)
We demonstrate that (i) low-grade ESS (LG-ESS) with YWHAE-NUTM2 fusions are not uncommon; (ii) they differ from their HG counterparts by the expression of genes involved in cell cycle/proliferation pathways and absence of mutation of the BCOR pathway, and by those involved in the immune response or angiogenesis and (iii) they may be identified by ER positivity in IHC
Summary
Endometrial stromal sarcoma (ESS) is a rare disease accounting for less than 1% of all uterine tumors [1]. In addition to morphological and immunohistochemical data, the integration of molecular methods enables a more precise diagnosis and nosological classification. It may be important for guiding clinical management in entities with different natural histories. YWHAE-fused HG-ESS are considered as high risk tumors for which adjuvant chemotherapy and radiotherapy is often recommended, and in the case of advanced disease, they are considered to be insensitive to hormonal therapies, and cytotoxic chemotherapy is considered appropriate [6,7]
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