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Targeted RNA expression profiling identifies high-grade endometrial stromal sarcoma as a clinically relevant molecular subtype of uterine sarcoma
- Source :
- Modern Pathology; May 2021, Vol. 34 Issue: 5 p1008-1016, 9p
- Publication Year :
- 2021
-
Abstract
- High-grade endometrial stromal sarcoma (HGESS) may harbor YWHAE-NUTM2A/Bfusion, ZC3H7B-BCORfusion, and BCORinternal tandem duplication (ITD). NTRK3upregulation and pan-Trk expression were reported in soft tissue lesions that share similar morphology and genetic abnormalities. To confirm these findings in HGESS, differential expression analysis was performed at gene level comparing 11 HGESS with 48 other uterine sarcomas, including 9 low-grade endometrial stromal sarcomas, 23 undifferentiated uterine sarcomas, and 16 leiomyosarcomas, using targeted RNA sequencing data. Pan-Trk immunohistochemistry was performed on 35 HGESS, including 10 tumors with RNA expression data, with genotypes previously confirmed by targeted RNA sequencing, fluorescence in situ hybridization, and/or genomic PCR. Unsupervised hierarchical clustering of the top 25% of differentially expressed probes identified three molecular groups: (1) high NTRK3, FGFR3, RET, BCOR, GLI1, and PTCH1and low ESR1expression; (2) low NTRK3, FGFR3, RET, BCOR, GLI1, and PTCH1and high ESR1expression; and (3) low NTRK3, FGFR3, RET, BCOR, GLI1, PTCH1, and ESR1expression. Among HGESS, 64% of tumors clustered in group 1, while 27% clustered in group 2. Cytoplasmic and/or nuclear pan-Trk staining of variable extent and intensity was seen in 91% of HGESS regardless of cyclin D1 and/or BCOR positivity. ER and PR expression was seen in 44% of HGESS despite ESR1downregulation. Two patients with ER and PR positive but ESR1downregulated stage I HGESS were treated with endocrine therapy, and both recurred at 12 and 36 months after primary resection. By RNA expression, HGESS appear homogenous and distinct from other uterine sarcomas by activation of kinases, including NTRK3, and sonic hedgehog pathway genes along with downregulation of ESR1. Most HGESS demonstrate pan-Trk staining which may serve as a diagnostic biomarker. ESR1downregulation is seen in some HGESS that express ER and PR which raises implications in the utility of endocrine therapy in these patients.
Details
- Language :
- English
- ISSN :
- 08933952 and 15300285
- Volume :
- 34
- Issue :
- 5
- Database :
- Supplemental Index
- Journal :
- Modern Pathology
- Publication Type :
- Periodical
- Accession number :
- ejs54445003
- Full Text :
- https://doi.org/10.1038/s41379-020-00705-6