Molecular classification of endometrial stromal sarcomas using RNA sequencing defines nosological and prognostic subgroups with different natural history.
Résumé
A series of 42 patients tumors diagnosed as endometrial stromal sarcomas (ESS) based on 15 the morphology but negative for JAZF1 and/or YWHAE rearrangement in FISH was analyzed by 16 RNA-sequencing. A chromosomal rearrangement was identified in 31 (74%) of the cases and a 17 missense mutation in known oncogenes / tumor suppressor genes in 11 (26%). Cluster analyses on 18 the expression profiles from this series together with a control cohort composed of 5 samples of Low 19 Grade ESS harboring a JAZF1-SUZ12 fusion, 1 High Grade ESS harboring a BCOR-ITD, 2 uterine 20 tumors resembling ovarian sex cord tumors, 2 samples each of uterine leiomyoma and 21 leiomyosarcomas and a series of BCOR-rearranged family of tumor (N=8), indicated that tumors 22 could be gather in three distinct subgroups: one mainly composed of BCOR-rearranged samples 23 that contained 7 ESS samples; one mainly composed of JAZF1-fused ESS (N=15) and the last 24 composed of various molecular subtypes (N=19). These three subgroups display different gene 25 signatures, different in silico cell cycle scores, and very different clinical presentations, natural 26 history and survival (Log-rank test, P=0.004). While YWHAE-NUTM2 fusion genes may be present 27 in both high and low grade ESS, the high-grade presenting with an additional BCOR or BCORL1 28 gene mutations. RNAseq brings clinically relevant molecular classification, enabling to reclassify 29 diseases and to guide therapeutic strategy. 30
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