title: Fusion of the EWS1 and WT1 genes as a result of the t(11;22)(p13;q12) translocation in desmoplastic small round cell tumors.
abstract: The isolation and molecular analysis of genes which cause and/or predispose to Wilms' tumor have yielded fascinating insights into the role of tissue-specific gene regulation in both development and disease processes. Analysis of the WT1 transcription factor has clearly established its role in Wilms' tumorigenesis and a broader role in both urogenital organogenesis and mesenchymal cell differentiation events. Clearly, loss of function mutations in WT1 is correlated with aberrant function as a regulator of gene expression, ultimately resulting in neoplastic transformation in the developing kidney. A question we have pursued is whether alterations of WT1 structure and/or function can be associated with other types of malignancies, possibly reflecting WT1's broader 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 translocation t(11;22)(p13;q12) involving the WT1 genomic locus. We have shown that the EWS1 gene fron chromosome 22q12 is fused to the WT1 gene in IADSRCT and that a fusion protein is produced which functions as a potent activator of transcription. Our results suggest that WT1 has sustained a gain-of function alteration as a results of this fusion and that the fusion gene functions as a dominant oncogene in this disease. Thus, the WT1 locus may be the target for both gain- and loss-of-function mutations resulting in different disease outcomes. A summary of our ongoing analysis of the EWS-WT1 fusion gene is presented.
authors.affiliation: Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: L E
authors.initials: LE
authors.lastname: Benjamin
authors.forename: W J
authors.initials: WJ
authors.lastname: Fredericks
authors.forename: F G
authors.initials: FG
authors.lastname: Barr
authors.forename: F J
authors.initials: FJ
authors.lastname: Rauscher
mesh_terms: D000328:Adult; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics*; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016162:Genes, Wilms Tumor / Q000235:genetics*; D006801:Humans; D008297:Male; D008648:Mesoderm / Q000502:physiology; D009154:Mutation / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D009857:Oncogenes / Q000235:genetics*; D012512:Sarcoma, Ewing / Q000235:genetics*; D018228:Sarcoma, Small Cell / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic / Q000235:genetics*; D025721:WT1 Proteins; D016335:Zinc Fingers / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; D025721:WT1 Proteins