Endometrial stromal sarcomas with BCOR‐rearrangement harbor MDM2 amplifications

Abstract

Recently a novel subtype of endometrial stromal sarcoma (ESS) defined by recurrent genomic alterations involving BCOR has been described (HGESS‐BCOR). We identified a case of HGESS‐BCOR with a ZC3H7B‐BCOR gene fusion, which harbored an amplification of the MDM2 locus. This index case prompted us to investigate MDM2 amplification in four additional cases of HGESS‐BCOR. Tumors were analyzed for MDM2 amplification by array‐based profiling of copy number alterations (CNAs) and fluorescence in situ hybridization (FISH), as well as for MDM2 expression by immunohistochemistry (IHC). Additionally, a cohort of other mesenchymal uterine neoplasms, including 17 low‐grade ESS, 6 classical high‐grade ESS with YWHAE ‐rearrangement, 16 uterine tumors resembling ovarian sex cord tumors, 7 uterine leiomyomas and 8 uterine leiomyosarcomas, was analyzed for CNAs in MDM2 . Copy number profiling identified amplification of the 12q15 region involving the MDM2 locus in all five HGESS‐BCOR. Subsequent validation analyses of three tumors confirmed MDM2 amplification using MDM2 FISH. Accordingly, IHC showed MDM2 overexpression in all analyzed cases. None of the other uterine neoplasms in our series, including tumors that are in the histopathological differential diagnoses of HGESS‐BCOR, showed copy number gains of MDM2 . Together, our results indicate that HGESS‐BCOR carries MDM2 amplifications, which has diagnostic implications and could potentially be used for targeted therapies in these clinically aggressive tumors.

Molecular pathogenesis and prognostication of "low‐grade'' and "high‐grade" endometrial stromal sarcoma

“…Furthermore, some but not all ZC3H7B/BCOR positive HG‐ESS are characterized by the presence of also the reciprocal transcript 51,52,56 whose role in tumorigenesis and/or progression is still unknown. Additionally, a new BCOR ‐rearranged HG‐ESS was recently reported by Kommoss et al 69 in which RNAseq identified a fusion between BCOR and LPP . The genic event behind the transcript resulted in overexpression of the C‐terminal, truncated BCOR protein but without generation of the chimera, that is, no coding part of LPP was involved.…”

“…The data obtained highlighted that the LG‐ESS pattern differed from that of HG‐ESS, and that, within the latter, distinct subgrouping of YWHAE ‐ and BCOR ‐rearranged tumors was possible 91 . The copy number‐profile was investigated by the same group in a series of uterine tumors that included LG‐ESS, HG‐ESS, UTROSCT, uterine leiomyomas, and uterine leiomyosarcomas 69 . The authors identified amplification of the MDM2 gene from chromosomal band 12q15 only in BCOR ‐rearranged HG‐ESS 69 .…”

“…Since such amplifications have not been identified in other mesenchymal uterine tumors, it is intriguing that Cotzia et al 70 suggested that UUS are unrecognized HG‐ESS. The discovery of MDM2 amplification opens up for potential use of targeted therapy in a subset of HG‐ESS 69 …”

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

“…Preclinical studies have previously shown that ESS may be sensitive to HDAC inhibition, and clinical data of the phase II trial of panobinostat in advanced sarcoma are consistent [25], even if only three ESSs were enrolled in the study. Moreover, a recent paper suggested that ESS with BCOR-rearrangement harbors MDM2 amplifications [26]. Among the four HG-ESS-BCOR of our series, only one (CLB_RNA_1549) carries a MDM2-CDK4 amplification ( Figure S9).…”

High-grade Endometrial Stromal Sarcoma With BCOR Gene Alterations is Recommended as an Independent Subtype of Endometrial Carcinoma: A Case Report

“…The HGESS in the current World Health Organization classi cation is limited to tumors characterized by high-grade round cell morphology and harboring t(10;17)(q22;p13) resulting in YWHAE-NUTM2 fusion (7), A recent study have described a rare subtype of ESS with high grade features and BCOR alterations, caused by either a gene fusion between BCOR and ZC3H7B or a mutually exclusive somatic internal tandem duplication of exon 15 of BCOR (8). In the only few cases reported in the literature to date, it has been proposed that it is more aggressive as another morphological variant of HGESS (4).…”