THE EWS-GENE REARRANGEMENT IN EWING TUMOR - KEY TO THE DISEASE

The family of Ewing tumors (ET) is characterised by a unique gene rear rangement which is represented by a translocation t(11;22) (q24;q12) o r a deletion del 22q12 in most cytogenetically analysable cases. The r ecent cloning of the underlying gene fusion provides the basis for the diagnostic detection of minimal amounts of residual tumor cells at re section margins. in blood and bone marrow. In addition, the very first steps in ET tumorigenesis can be studied on a functional basis. In th is study, a variety of fusion products were identified with a sensitiv ity of 10(-6) by means of RT-PCR. In 20 of 22 ET, a gene rearrangement was identified which resulted in the substitution of the effector dom ain of one of the closely related DNA-binding oncogenes, FLI-1 or ERG, by the transactivating domain of a new gene, EWS. Presumably, the onc ogene and consequently its target genes are activated by this type of translocation. If the EWS domain was replaced with a transcriptionally irrelevant domain by transfection of a recombinant gene into ET cells , competition with the endogenous chimeric oncogene-product for DNA-bi nding was observed resulting in a partial growth inhibition. Activatio n of FLI-1 has been previously shown to occure as a primary event in F riend virus induced mouse erythroleukemia. During progression of this disease. inactivating p53 mutations have been observed frequently. In contrast, such aberrations were found to be extremely rare in ET.