Novel BCOR-MAML3 and ZC3H7B-BCOR Gene Fusions in Undifferentiated Small Blue Round Cell Sarcomas.
Novel BCOR-MAML3 and ZC3H7B-BCOR Gene Fusions in Undifferentiated Small Blue Round Cell Sarcomas.
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新型的BCOR-MAML3和ZC3H7B-BCOR基因融合在未分化的小蓝色圆形细胞肉瘤中。
DOI：
10.1097/pas.0000000000000591
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发表时间：
2016-04
期刊：
影响因子：
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通讯作者：
Antonescu CR
中科院分区：
文献类型：
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作者：
Specht K;Zhang L;Sung YS;Nucci M;Dry S;Vaiyapuri S;Richter GH;Fletcher CD;Antonescu CR
小蓝圆细胞肿瘤（SBRCTs）是一组异质性肿瘤，由于形态学、免疫组化和临床特征重叠而难以诊断。大约三分之二的EWSR 1阴性SBRCT与CIC-DUX 4相关融合相关，而另一个小子集显示BCOR-CCNB 3 X染色体旁着丝粒倒位。应用配对末端RNA测序的SBRCT指数的情况下，44岁的男性，我们确定了一种新的BCOR-MAML 3嵌合融合，这是通过RT-PCR和FISH技术验证。然后，我们通过FISH筛选了总共75个缺乏EWSR 1、FUS、SYT、CIC和BCOR-CCNB 3异常的SBRCT，以检测BCOR断裂探针，从而检测在典型X染色体倒位之外的潜在复发性BCOR基因重排。事实上，8/75（11%）SBRCT显示出不同的BCOR基因重排，其中2例分别显示BCOR-MAML 3或ZC 3 H7 B-BCOR融合，而在其余4例中未检测到融合伴侣。与经典尤文肉瘤或CIC-DUX 4阳性SBRCT相比，BCOR-MAML 3阳性指数病例的基因表达显示出独特的转录谱，HOX基因签名上调。我们还将BCOR重排的SRBCT的临床病理特征与一组BCOR-CCNB 3倒位阳性病例进行了比较，并将我们的11例病例与42例已发表病例的荟萃分析相结合。BCOR-CCNB 3阳性肿瘤优先发生在儿童和骨中，而BCOR重排的SBRCTs则发生在年轻人中，具有不同的解剖分布。此外，BCOR重排的肿瘤通常显示梭形细胞区域，在交叉的纤维束中界限清楚或与圆形细胞成分混合，这与大多数其他融合阳性SBRCT不同，并与低分化滑膜肉瘤有组织学重叠。
Small blue round cell tumors (SBRCTs) are a heterogenous group of tumors that are difficult to diagnose due to overlapping morphologic, immunohistochemical and clinical features. About two-thirds of EWSR1-negative SBRCTs are associated with CIC-DUX4 related fusions, while another small subset shows BCOR-CCNB3 X-chromosomal paracentric inversion. Applying paired-end RNA sequencing to an SBRCT index case of a 44 year-old male, we identified a novel BCOR-MAML3 chimeric fusion, which was validated by RT-PCR and FISH techniques. We then screened a total of 75 SBRCTs lacking EWSR1, FUS, SYT, CIC and BCOR-CCNB3 abnormalities, for BCOR break-apart probes by FISH to detect potential recurrent BCOR gene rearrangements, outside the typical X-chromosomal inversion. Indeed, 8/75 (11%) SBRCTs showed distinct BCOR gene rearrangements, with 2 cases each showing either a BCOR-MAML3 or the alternative ZC3H7B-BCOR fusion, while no fusion partner was detected in the remaining 4 cases. Gene expression of the BCOR-MAML3 positive index case showed a distinct transcriptional profile with upregulation of HOX-gene signature, compared to classic Ewing sarcoma or CIC-DUX4-positive SBRCTs. The clinicopathologic features of the SRBCTs with alternative BCOR rearrangements were also compared with a group of BCOR-CCNB3 inversion positive cases, combining 11 from our files with a meta-analysis of 42 published cases. The BCOR-CCNB3-positive tumors occurred preferentially in children and in bone, in contrast to alternative BCOR-rearranged SBRCTs which presented in young adults, with a variable anatomic distribution. Furthermore BCOR-rearranged tumors often displayed spindle cell areas, either well-defined in intersecting fascicles or blending with the round cell component, which appears distinct from most other fusion-positive SBRCTs and shares histologic overlap with poorly differentiated synovial sarcoma.