NTRK3 overexpression in undifferentiated sarcomas with YWHAE and BCOR genetic alterations
| Autor: | Brendan C. Dickson, Pedram Argani, Cristina R. Antonescu, Yu Chien Kao, Leonard H. Wexler, David Swanson, Rita Alaggio, Yun Shao Sung, William D. Tap |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Pathology medicine.medical_specialty Solitary fibrous tumor PMMTI Biology NTRK3 Article Pathology and Forensic Medicine 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Proto-Oncogene Proteins 14-3-3 proteins gene expression regulation neoplastic humans proto-oncogene proteins receptor trkC repressor proteins sarcoma up-regulation medicine Humans YWHAE Receptor trkC BCOR round cell sarcoma Cancer Sarcoma medicine.disease Synovial sarcoma Up-Regulation CCSK Gene Expression Regulation Neoplastic Repressor Proteins 030104 developmental biology 14-3-3 Proteins 030220 oncology & carcinogenesis Immunohistochemistry Clear cell |
| Zdroj: | Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc |
| Popis: | The BCOR family of tumors includes a number of undifferentiated sarcomas, occurring in various age groups and anatomic sites, characterized by a spindle and round cell phenotype and diffuse immunoreactivity for BCOR. Prior RNA sequencing data revealed that NTRK3 was a top-upregulated gene in BCOR-CCNB3 sarcomas. In this study, we investigate a large cohort of tumors harboring BCOR/YWHAE genetic alterations for NTRK3 upregulation at both the mRNA and protein levels, compared with other sarcoma types. Pan-Trk immunohistochemistry was assessed for intensity and extent. A correlation between NTRK3 expression and the type of BCOR alteration and BCOR immunoreactivity was also performed. Most soft tissue undifferentiated round cell sarcomas with YWHAE or BCOR rearrangements or BCOR internal tandem duplications (ITD) showed NTRK3, but not NTRK1 or NTRK2, upregulation by RNA sequencing data analysis. Cytoplasmic pan-Trk immunoreactivity was also observed in most soft tissue round cell sarcomas with YWHAE rearrangements (100%), BCOR ITD (80%), and BCOR-CCNB3 fusions (67%), as well as clear cell sarcomas of kidney (75%), another BCOR family tumor, and ossifying fibromyxoid tumors with ZC3H7B-BCOR fusion (100%), with variable staining intensity and extent. Pan-Trk staining was also seen in solitary fibrous tumors (100%) and less frequently in synovial sarcoma and Ewing sarcoma, but rarely in other sarcomas tested. Tumors harboring rare fusion variants of BCOR, such as BCOR-CHD9, a novel fusion identified by targeted RNA sequencing, and KMT2D-BCOR, were also positive for pan-Trk staining and NTRK3 overexpression. In conclusion, NTRK3 upregulation resulting in pan-Trk overexpression is common in the BCOR family of tumors as well as in subsets of BCOR-expressing sarcomas through alternative mechanisms. The therapeutic implication of this finding awaits further investigation. |
| Databáze: | OpenAIRE |
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