Endometrial Stromal Sarcomas With BCOR Internal Tandem Duplication and Variant BCOR/BCORL1 Rearrangements Resemble High-grade Endometrial Stromal Sarcomas With Recurrent CDK4 Pathway Alterations and MDM2 Amplifications.

The distinction between low-grade and high-grade endometrial stromal sarcomas (LGESS, HGESS) is increasingly defined by genetics. Recently, variant genomic alterations involving BCOR or BCORL1 have been reported in endometrial stromal sarcoma (ESS), although it remains unclear whether these justify a diagnosis of LGESS or HGESS. In this study, we describe clinicopathologic and molecular features of ESS with such alterations to help clarify their classification in the spectrum of ESS. We collected a cohort of 13 ESS harboring variant alteration involving BCOR (6 with internal tandem duplication, 1 with EP300::BCOR fusion, 1 with BCOR::LPP fusion) and BCORL1 ( 4 with JAZF1::BCORL1 fusion, 1 with EPC1::BCORL1 fusion). The median patient age at primary diagnosis was 51 years (range: 18 to 70 y). Median tumor size at primary diagnosis was 9.3 cm (range: 4.5 to 21 cm), and extrauterine disease spread (stage IIIB-C) was present in 27%. The tumors were composed of round to spindled cells with cellularity and cytologic atypia ranging from mild to marked and a median mitotic count of 18/10 HPFs (range: 2 to 85/10 HPFs). At least focally myopermeative growth was noted in 8/8 assessable cases. Of 12 patients with follow-up data (median: 25 mo), 4 patients died of disease and 3 were alive with recurrent disease. Unsupervised hierarchical clustering of DNA methylation data together with a large cohort of uterine mesenchymal tumors that included YWHAE::NUTM2 and Z C3H7B::BCOR HGESS and molecularly confirmed LGESS revealed a common methylation signature for all ESS with variant BCOR and BCORL1 alterations and HGESS with YWHAE::NUTM2 and ZC3H7B::BCOR gene fusion. Copy number analysis revealed amplifications of CDK4 and MDM2 , as well as homozygous deletions of CDKN2A/B and NF1 in a subset of tumors. Our results indicate that ESS with BCOR internal tandem duplication and variant BCOR and BCORL1 rearrangements clinically and molecularly resemble conventional HGESS.

Kommoss FKF ，Chiang S ，Köbel M ，Koelsche C ，Chang KT ，Irving JA ，Dickson B ，Thiryayi S ，Rouzbahman M ，Rasty G ，von Deimling A ，Lee CH ，Turashvili G ... -  《-》

Endometrial stromal sarcomas with BCOR-rearrangement harbor MDM2 amplifications.

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.

Kommoss FK ，Chang KT ，Stichel D ，Banito A ，Jones DT ，Heilig CE ，Fröhling S ，Sahm F ，Stenzinger A ，Hartmann W ，Mechtersheimer G ，Sinn HP ，Schmidt D ，Kommoss F ，von Deimling A ，Koelsche C ... -  《Journal of Pathology Clinical Research》

BCOR Internal Tandem Duplication in High-grade Uterine Sarcomas.

Mariño-Enriquez A ，Lauria A ，Przybyl J ，Ng TL ，Kowalewska M ，Debiec-Rychter M ，Ganesan R ，Sumathi V ，George S ，McCluggage WG ，Nucci MR ，Lee CH ，Fletcher JA ... -  《-》

Genomic profiling of BCOR-rearranged uterine sarcomas reveals novel gene fusion partners, frequent CDK4 amplification and CDKN2A loss.

Genomic alterations of BCOR via ZC3H7B-BCOR fusion or BCOR internal tandem duplication (ITD) define a subset of endometrial stromal sarcoma (ESS). The goals of this study were to: 1) determine the molecular landscape of BCOR-rearranged ESS, 2) to identify novel BCOR fusion gene partners in ESS and their associated clinicopathological characteristics, and 3) to potentially unravel targetable genomic alterations in BCOR-mutated ESS. A retrospective database search of a CLIA-certified molecular laboratory was performed for uterine sarcomas that contained BCOR rearrangements or BCOR ITD. The cases were previously assayed by comprehensive genomic profiling via both DNA- and RNA-based targeted next generation sequencing during the course of clinical care. Clinicopathological and genomic data was centrally re-reviewed. We identify largest cohort of BCOR-rearranged ESS to date (n = 40), which included 31 cases with canonical ZC3H7B-BCOR fusion as well as 8 cases with novel BCOR gene rearrangement partners, such as BCOR-L3MBTL2, EP300-BCOR, BCOR-NUTM2G, BCOR-RALGPS1, BCOR-MAP7D2, RGAG1-BCOR, ING3-BCOR, BCOR-NUGGC, KMT2D-BCOR, CREBBP-BCOR and 1 case with BCOR internal rearrangement. Re-review of cases with novel rearrangements demonstrated sarcomas with spindle, epithelioid or small round cell components and frequent myxoid stromal change. Comprehensive genomic profiling revealed high frequency of CDK4 and MDM2 amplification in 38% and 45% of BCOR-rearranged cases, respectively, and homozygous deletion of CDKN2A, which encodes an inhibitor of CDK4 in 28% of cases. Notably, CDK4 and MDM2 amplification was absent in all cases from 15 different ESS cases harboring BCOR ITD. Alterations of CDK4 pathway members, for which targeted therapy is clinically available (i.e. palbociclib), via CDK4 amplification or CDKN2A loss, contributes to the pathogenesis of BCOR-rearranged uterine sarcomas, which may have therapeutic implications.

Lin DI ，Hemmerich A ，Edgerly C ，Duncan D ，Severson EA ，Huang RSP ，Ramkissoon SH ，Connor YD ，Shea M ，Hecht JL ，Ali SM ，Vergilio JA ，Ross JS ，Elvin JA ... -  《-》

Clinicopathological and genomic characterization of BCORL1-driven high-grade endometrial stromal sarcomas.

BCORL1 is a transcriptional corepressor homologous to BCOR. We describe 12 BCORL1-altered uterine sarcomas with striking resemblance to BCOR-altered endometrial stromal sarcoma (BCOR-ESS), including 5 with BCORL1 rearrangements (JAZF1-BCORL1, EP300-BCORL1, or internal BCORL1 rearrangement), 5 with inactivating BCORL1 mutations (T513fs*22, P600fs*1, R945*, R1196*, or R1265fs*4) and 2 with homozygous BCORL1 deletion. The median patient age was 57.5 years (range 33-79). An association with aggressive clinical behavior was identified. Diagnoses assigned prior to genomic testing varied: 7 tumors were previously diagnosed as ESS, 2 as high-grade uterine sarcomas, 2 as myxoid uterine leiomyosarcomas, and 1 as a uterine spindle cell neoplasm consistent with leiomyosarcoma. Tumors harbored frequent gelatinous, mucomyxoid-like appearance by gross examination and unique histology with morphological overlap with BCOR-ESS. Key microscopic features included (1) a spindle cell appearance, most often with at least focal myxoid stroma, (2) variable amounts of hypocellular fibromyxoid spindle areas with lower grade atypia and/or (3) variable amounts of epithelioid areas with higher grade atypia. Specifically, spindle and epithelioid components were present in 100 and 75% of sarcomas, respectively; myxoid stroma was identified in 83%, collagen plaques or fibrosis in 50%, and high-grade nuclear atypia was present in 42%. Like BCOR-ESS, 50% of BCORL1-altered sarcomas exhibited CDK4 amplification or CDKN2A loss. In contrast, 33% harbored NF1 alterations, while 25% had other alterations in the NF2-mTOR pathway, expanding potential therapeutic targets. In conclusion, inactivating BCORL1 genomic alterations may define a distinct subset of high-grade endometrial stromal sarcomas with biological overlap with BCOR-ESS, both of which may mimic myxoid leiomyosarcomas.

Lin DI ，Huang RSP ，Mata DA ，Decker B ，Danziger N ，Lechpammer M ，Hiemenz M ，Ramkissoon SH ，Ross JS ，Elvin JA ... -  《-》