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Molecular diagnosis of ewing family tumors: too many fusions... ?

In the field of sarcoma molecular diagnosis, the "test" most frequently requested is for the gene fusions generated by the chromosomal translocations in Ewing family tumors (EFTs). Of note, this test is perhaps the most complicated of all of the molecular assays in the sarcoma diagnostic toolbox. Starting with the frequent 11;22 translocation involving the EWS gene on chromosome 22 and the FLI1 gene on chromosome 11, the chromosome breakpoints are spread among four introns in the EWS gene and six introns in the FLI1 gene to give a large number of possible EWS-FLI1 fusion products.1 The size of the fusion transcripts can vary over a 700-bp range, thereby necessitating cautious investigation of a large range of product sizes in diagnostic reverse transcription-polymerase chain reaction (RT-PCR) assays. To increase the complexity further, a relatively frequent variant 21;22 chromosomal translocation generates a fusion of EWS to ERG, which encodes an ETS domain-containing transcription factor highly related to FLI1 with a comparable distribution of chromosomal breakpoints.1 Next, as described in the article by Wang and associates in this issue of The Journal of Molecular Diagnostics,2 the complexity continues to rise as there are three additional translocations [t(2;22), t(7;22), and t(17;22)] that juxtapose EWS to genes, encoding three additional members of the ETS transcription factor family (FEV, ETV1, and E1AF, respectively) in small numbers of EFT cases. In addition to these rare variant fusions, there is also a second set of rare variants involving the FUS gene, which encodes an RNA-binding protein highly related to EWS. This second set includes a 16;21 translocation in which FUS is juxtaposed to ERG,3 which was found in a small group of cases and, as described by Ng and colleagues4 also in this issue of the JMD, a FUS-FEV fusion resulting from a novel 2;16 translocation found in a single case. Based on these collective findings, a definitive investigation of the gene fusions associated with EFT is, to put it simply, a daunting task.