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

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.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Calmodulin-Binding Proteins
  • ERG protein, human
  • EWSR1 protein, human
  • FUS protein, human
  • RNA-Binding Protein EWS
  • RNA-Binding Protein FUS
  • RNA-Binding Proteins
  • Trans-Activators
  • Transcriptional Regulator ERG