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

• Published in: Genes chromosomes & cancer 2016-04, Vol.55 (4), p.340-349
• Main Authors: Chen, Sonja, Deniz, Kemal, Sung, Yun-Shao, Zhang, Lei, Dry, Sarah, Antonescu, Cristina R.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Calmodulin-Binding Proteins - genetics; Child; Child, Preschool; Cohort Studies; Female; Gene Rearrangement; Humans; In Situ Hybridization, Fluorescence; Male; Middle Aged; RNA-Binding Protein EWS; RNA-Binding Protein FUS - genetics; RNA-Binding Proteins - genetics; Sarcoma, Ewing - genetics; Sarcoma, Ewing - pathology; Trans-Activators - genetics; Transcriptional Regulator ERG; Young Adult
• ISSN: 1045-2257; 1098-2264
• DOI: 10.1002/gcc.22336

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. © 2015 Wiley Periodicals, Inc.