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.

中文翻译：

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NTRK3 在具有 YWHAE 和 BCOR 基因改变的未分化肉瘤中过表达。

BCOR 肿瘤家族包括许多未分化肉瘤，发生在不同年龄组和解剖部位，其特征是梭形和圆形细胞表型和 BCOR 的弥漫性免疫反应性。先前的 RNA 测序数据显示 NTRK3 是 BCOR-CCN​​B3 肉瘤中上调的基因。在这项研究中，我们调查了一大群肿瘤，这些肿瘤与其他肉瘤类型相比，在 mRNA 和蛋白质水平上都存在 BCOR/YWHAE 基因改变，导致 NTRK3 上调。评估了 Pan-Trk 免疫组织化学的强度和范围。还进行了 NTRK3 表达与 BCOR 改变类型和 BCOR 免疫反应性之间的相关性。大多数具有 YWHAE 或 BCOR 重排或 BCOR 内部串联重复 (ITD) 的软组织未分化圆形细胞肉瘤显示 NTRK3，但不​​显示 NTRK1 或 NTRK2，通过 RNA 测序数据分析上调。在大多数具有 YWHAE 重排 (100%)、BCOR ITD (80%) 和 BCOR-CCN​​B3 融合 (67%) 的软组织圆细胞肉瘤以及肾透明细胞肉瘤中也观察到细胞质泛 Trk 免疫反应性 (75 %)、另一种 BCOR 家族肿瘤和具有 ZC3H7B-BCOR 融合 (100%) 的骨化性纤维粘液样肿瘤，具有可变的染色强度和范围。Pan-Trk 染色也见于孤立性纤维瘤 (100%)，较少见于滑膜肉瘤和尤文肉瘤，但很少见于其他受检肉瘤。含有罕见 BCOR 融合变体的肿瘤，如 BCOR-CHD9（一种通过靶向 RNA 测序鉴定的新型融合体）和 KMT2D-BCOR，也对泛 Trk 染色和 NTRK3 过表达呈阳性。综上所述，NTRK3 上调导致泛 Trk 过度表达在 BCOR 肿瘤家族以及通过替代机制表达 BCOR 的肉瘤亚群中很常见。这一发现的治疗意义有待进一步研究。