BCOR Overexpression Is a Highly Sensitive Marker in Round Cell Sarcomas With BCOR Genetic Abnormalities
BCOR Overexpression Is a Highly Sensitive Marker in Round Cell Sarcomas With BCOR Genetic Abnormalities
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DOI：
10.1097/pas.0000000000000697
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发表时间：
2016-12-01
影响因子：
5.6
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.
随着下一代测序技术的出现，EWSR1阴性的小蓝圆细胞肿瘤(SBRCT)中出现了越来越多的新的基因融合和其他异常。在这方面，具有BCOR基因融合(BCOR-CCNB3，BCOR-MAML3)、BCOR内部串联复制(ITD)或YWHAE-NUTM2B的SBRCT的子集共享转录特征，包括高BCOR mRNA表达，以及相似的组织学特征。此外，其他肿瘤，如肾透明细胞肉瘤(CCSK)和婴儿期原始黏液样间充质瘤也显示BCOR ITDS和BCOR基因的高表达。这些不同的BCOR基因改变的分子诊断需要一种复杂的方法学，包括定制的BAC荧光原位杂交(FISH)探针和逆转录聚合酶链式反应分析。由于这些肿瘤表现出高水平的BcoR过表达，无论涉及的遗传机制是常规的基因融合还是ITD，我们试图研究抗BcoR的单抗克隆C-10(sc-514576)作为具有bcor基因异常的肉瘤的免疫组织化学标记的性能。因此，我们评估了BCOR在病理和遗传学特征良好的25个SBRCT队列中的表达，这些队列跨越了各种BCOR相关融合和ITD以及YWHAE-NUTM2B融合。此外，我们还包括相关的病理实体，如8个CCSKs和其他融合了BCOR基因的肉瘤。作为对照组，我们包括20例有各种(非BCOR)遗传异常的SBRCT，10例融合阴性的SBRCT，74例滑膜肉瘤，29例横纹肌肉瘤和其他类型的肉瘤。此外，我们评估了同一研究组的SATB2免疫反应性，因为这些肿瘤也显示SATB2 mRNA上调。所有与BCOR-MAML3和BCOR-CCNB3融合的SBRCT，以及大多数与BCOR ITD融合的SBRCT(93%)，所有CCSKs都显示出强烈的弥漫性核BCOR免疫反应。此外，所有携带YWHAE-NUTM2B的SBRCT均为阳性。SATB2在YWHAE-NUTM2B、BCOR-MAML3、BCOR ITD(75%)、BCOR-CCNB3(71%)和CCSKs亚型(33%)中也呈阳性表达。综上所述，BCOR免疫组织化学染色是诊断SBRCT和CCSKs合并BCOR异常和YWHAE重排的高度敏感的标记物，可作为这些不同分子亚群的有用诊断标记物。SATB2免疫反应也存在于大多数这类肿瘤中。
With the advent of next-generation sequencing, an increasing number of novel gene fusions and other abnormalities have emerged recently in the spectrum of EWSR1-negative small blue round cell tumors (SBRCTs). In this regard, a subset of SBRCTs harboring either BCOR gene fusions (BCOR-CCNB3, BCOR-MAML3), BCOR internal tandem duplications (ITD), or YWHAE-NUTM2B share a transcriptional signature including high BCOR mRNA expression, as well as similar histologic features. Furthermore, other tumors such as clear cell sarcoma of kidney (CCSK) and primitive myxoid mesenchymal tumor of infancy also demonstrate BCOR ITDs and high BCOR gene expression. The molecular diagnosis of these various BCOR genetic alterations requires an elaborate methodology including custom BAC fluorescence in situ hybridization (FISH) probes and reverse transcription polymerase chain reaction assays. As these tumors show high level of BCOR overexpression regardless of the genetic mechanism involved, either conventional gene fusion or ITD, we sought to investigate the performance of an anti-BCOR monoclonal antibody clone C-10 (sc-514576) as an immunohistochemical marker for sarcomas with BCOR gene abnormalities. Thus we assessed the BCOR expression in a pathologically and genetically well-characterized cohort of 25 SBRCTs, spanning various BCOR-related fusions and ITDs and YWHAE-NUTM2B fusion. In addition, we included related pathologic entities such as 8 CCSKs and other sarcomas with BCOR gene fusions. As a control group we included 20 SBRCTs with various (non-BCOR) genetic abnormalities, 10 fusion-negative SBRCTs, 74 synovial sarcomas, 29 rhabdomyosarcomas, and other sarcoma types. In addition, we evaluated the same study group for SATB2 immunoreactivity, as these tumors also showed SATB2 mRNA upregulation. All SBRCTs with BCOR-MAML3 and BCOR-CCNB3 fusions, as well as most with BCOR ITD (93%), and all CCSKs showed strong and diffuse nuclear BCOR immunoreactivity. Furthermore, all SBRCTs with YWHAE-NUTM2B also were positive. SATB2 stain was also positive in tumors with YWHAE-NUTM2B, BCOR-MAML3, BCOR ITD (75%), BCOR-CCNB3 (71%), and a subset of CCSKs (33%). In conclusion, BCOR immunohistochemical stain is a highly sensitive marker for SBRCTs and CCSKs with BCOR abnormalities and YWHAE-rearrangements and can be used as a useful diagnostic marker in these various molecular subsets. SATB2 immunoreactivity is also present in the majority of this group of tumors.