NTRK3 overexpression in undifferentiated sarcomas with YWHAE and BCOR genetic alterations
NTRK3 overexpression in undifferentiated sarcomas with YWHAE and BCOR genetic alterations
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DOI：
10.1038/s41379-020-0495-2
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发表时间：
2020-02-07
期刊：
影响因子：
7.5
通讯作者：
Antonescu, Cristina R.
中科院分区：
文献类型：
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作者：
Kao, Yu-Chien;Sung, Yun-Shao;Antonescu, Cristina R.
BCOR肿瘤家族包括许多未分化的肉瘤，发生在不同的年龄组和解剖部位，以梭形和圆形细胞表型为特征，对BCOR呈弥漫性免疫反应。先前的RNA测序数据显示，NTRK3是BCOR-CCNB3肉瘤中的一个上调基因。在这项研究中，我们调查了与其他肉瘤类型相比，具有NTRK3基因上调的BCOR/YWHAE基因改变的大量肿瘤在mRNA和蛋白水平上的表达。对PAN-Trk免疫组织化学染色强度和范围进行评估。NTRK3的表达与BCOR改变的类型和BCOR免疫反应性也进行了相关性分析。通过RNA测序数据分析，大多数YWHAE或BCOR重排或BCOR内部串联重复(ITD)的软组织未分化圆细胞肉瘤显示NTRK3上调，但NTRK1或NTRK2未见上调。在YWHAE重排(100%)、BCOR ITD(80%)和BCOR-CCNB3融合(67%)的大多数软组织圆形细胞肉瘤以及肾透明细胞肉瘤(75%)、BCOR家族肿瘤和骨化纤维粘液样肿瘤(100%)中也观察到PAN-Trk免疫反应阳性，染色强度和程度不等。PAN-Trk染色也见于孤立性纤维性肿瘤(100%)，在滑膜肉瘤和尤文肉瘤中较少见，但在其他肉瘤中很少见。含有罕见的BCOR融合变异体的肿瘤，如靶向RNA测序鉴定的新型融合基因BCOR-CHD9和KMT2D-BCOR，PAN-Trk染色和NTRK3过表达也呈阳性。总之，NTRK3上调导致PAN-Trk过度表达在BCOR肿瘤家族和表达BCOR的肉瘤亚群中是常见的，通过不同的机制。这一发现的治疗意义有待进一步调查。
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.