FUSION OF THE EWS1 AND WT1 GENES AS A RESULT OF THE T(11-22)(13-Q12) TRANSLOCATION IN DESMOPLASTIC SMALL ROUND-CELL TUMORS

The isolation and molecular analysis of genes which cause and/or predi spose to Wilms' tumor have yielded fascinating insights into the role of tissue-specific gene regulation in both development and disease pro cesses. Analysis of the WT1 transcription factor has clearly establish ed its role in Wilms' tumorigenesis and a broader role in both urogeni tal organogenesis and mesenchymal cell differentiation events. Clearly , loss of function mutations in WT1 is correlated with aberrant functi on as a regulator of gene expression, ultimately resulting in neoplast ic transformation in the developing kidney. A question we have pursued is whether alterations of WT1 structure and/or function can be associ ated with other types of malignancies, possibly reflecting WT1's broad er role in mesenchymal differentiation. To this end, we have analyzed a rare solid tumor designated Intra-Abdominal Desmoplastic Small Round Cell Sarcoma (IADSRCT) which often displays a recurrent chromosomal t ranslocation t(11;22)(p13;q12) involving the WT1 genomic locus. We hav e shown that the EWS1 gene from chromosome 22q12 is fused to the WT1 g ene in IADSRCT and that a fusion protein is produced which functions a s a potent activator of transcription. Our results suggest that WT1 ha s sustained a gain-of-function alteration as a result of this fusion a nd that the fusion gene functions as a dominant oncogene in this disea se. Thus, the WT1 locus may be the target for both gain- and loss-of-f unction mutations resulting in different disease outcomes. A summary o f our ongoing analysis of the EWS-WT1 fusion gene is presented. (C) 19 96 Wiley-Liss, Inc.