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 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.

Predictive and prognostic transcriptomic biomarkers in soft tissue sarcomas

“…A recent study also showed that small round cell sarcomas with distinct fusions (e.g., CIC-fused and BCOR-rearranged tumours) had unique transcriptomic profiles 25 . Further reinforcing the idea that transcriptomics has a role in the molecular classification of fusion driven sarcomas, the same group showed that consensus clustering of gene expression data in endometrial stromal sarcomas (ESS) was capable of identifying a high grade group comprised of tumours harbouring BCOR rearrangements, and a low grade group composed of tumours with a fusion of a PRC2 zinc finger protein (such as JAZF1 and PHF1) 26 . Interestingly, YWHAE-NUTM2 positive ESS which is typically considered a clinically aggressive subtype was found to be split in the high grade and low grade clusters, indicative of molecular heterogeneity within this fusion positive ESS 26 .…”

Update on Endometrial Stromal Tumours of the Uterus

“…Novel fusions that have been recently detected using RNA sequencing include KAT6B-KANSL1, RNF111-ARID2, ESR1-NCOA3, PTCH1-GLI1, SYNGAP1-JAZF1, PHF21A-NFIA, PHF21A-CETP, ACTB-GLI1 and GREB1-NCOA2 [ 89 ].…”

“…Some LG-ESSs harbouring YWHAE-NUTM2 fusion, which is a molecular characteristic of high-grade endometrial sarcomas, have also been reported [ 89 , 90 ].…”

“…Mainly NUTM2A and NUTM2B have been reported to form fusion with YWHAE as alternative gene fusion partners [ 7 , 97 ]. In a more recent report, NUTM2E (paralog of NUTM2B ) has also been detected as an alternative gene fusion partner [ 89 ].…”

“…EPC1-BCOR, EPC1-SUZ12 and BRD8-PHF1 fusions have also been reported, but they are rare [ 63 , 86 ]. A few cases have demonstrated a nucleotide variation with mutation in BCOR (NM_017745 ( BCOR exon 4):c.2570_2571del (p.E857fs) and in BCORL1 (NM_021946 ( BCORL1 exon 7):c.A4256T (p.K1419I) [ 89 ], in addition to the presence of YWHAE-NUTM2E fusion.…”