伴有ERG基因重排的尤因肉瘤:一项聚焦于FUS-ERG发生率及荧光原位杂交检测EWSR1-ERG融合常见陷阱的分子研究

Ewing sarcoma with ERG gene rearrangements: A molecular study focusing on the prevalence of FUS-ERG and common pitfalls in detecting EWSR1-ERG fusions by FISH.

作者信息

Chen Sonja, Deniz Kemal, Sung Yun-Shao, Zhang Lei, Dry Sarah, Antonescu Cristina R

机构信息

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.

Department of Pathology, Erciyes University, Kayseri, Turkey.

出版信息

Genes Chromosomes Cancer. 2016 Apr;55(4):340-9. doi: 10.1002/gcc.22336. Epub 2015 Dec 22.

Abstract

The genetics of Ewing sarcoma (ES) are characterized by a canonical fusion involving EWSR1 gene and a member of the ETS family of transcription factors, such as FLI1 and ERG. In fact, ERG gene rearrangements represent the second most common molecular alteration, with EWSR1-ERG being identified in 5-10% of cases, while only a handful of reports document a FUS-ERG fusion. In this study, we focus on ES with ERG gene abnormalities, specifically to investigate the prevalence and clinicopathologic features of FUS-ERG fusions in a large cohort of small blue round cell tumors (SBRCTs) and compare to the eight reported FUS-positive ES. Among the 85 SBRCTs tested, seven (8.2%) cases harbored FUS gene rearrangements; six fused to ERG and one with FEV. During this investigation we came across a number of ERG-rearranged ES lacking both EWSR1 and FUS abnormalities by FISH. In one case, RNA sequencing identified an EWSR1-ERG transcript despite the negative EWSR1 rearrangements by FISH. Additional 3-color FISH fusion assay demonstrated the fusion of EWSR1 and ERG signals in all four cases negative for break-apart EWSR1 FISH. These results emphasize a potential pitfall of relying on EWSR1 FISH assay alone for diagnosis of ES. In cases with classic morphology and/or strong CD99 and ERG immunoreactivity, additional molecular testing should be applied, such as ERG FISH or RT-PCR/next generation sequencing, for a more definitive diagnosis. Although our study group is small, there were no differences noted between the clinical, morphologic features and immunoprofile of the different subsets of ERG-rearranged SBRCTs.

摘要

尤因肉瘤(ES)的遗传学特征是EWSR1基因与ETS转录因子家族成员(如FLI1和ERG)发生典型融合。事实上,ERG基因重排是第二常见的分子改变,EWSR1-ERG在5%-10%的病例中被发现,而仅有少数报告记录了FUS-ERG融合。在本研究中,我们聚焦于具有ERG基因异常的ES,具体研究一大组小蓝圆细胞肿瘤(SBRCT)中FUS-ERG融合的发生率和临床病理特征,并与8例报告的FUS阳性ES进行比较。在检测的85例SBRCT中,7例(8.2%)存在FUS基因重排;6例与ERG融合,1例与FEV融合。在此次研究中,我们通过荧光原位杂交(FISH)发现了一些既无EWSR1也无FUS异常的ERG重排ES。在1例病例中,尽管FISH检测EWSR1重排为阴性,但RNA测序鉴定出了EWSR1-ERG转录本。另外的三色FISH融合检测显示,在所有4例EWSR1 FISH分裂检测为阴性的病例中,EWSR1和ERG信号发生了融合。这些结果强调了仅依靠EWSR1 FISH检测诊断ES可能存在的陷阱。对于具有经典形态和/或强CD99及ERG免疫反应性的病例,应进行额外的分子检测,如ERG FISH或逆转录聚合酶链反应/下一代测序,以获得更明确的诊断。尽管我们的研究组规模较小,但不同亚组的ERG重排SBRCT在临床、形态学特征和免疫表型方面未发现差异。

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