Involvement of EWS Proto-oncogene in Desmoplastic Small Round Cell Tumor

다국어 초록 (Multilingual Abstract)

The transformation process involves genetic changes to cellular proto-oncogenes and tumor suppressor genes. The consequences of these genetic alterations are to confer a growth advantage to the cell. Three genetic mechanisms activate oncogenes or inactivate tumor suppressor genes in human neoplasms: (ⅰ) mutations, (ⅱ) gene amplification, and (ⅲ) chromosomal rearrangements. In many human cancers, tumor-specific chromosomal rearrangements are known to create chimeric products with the ability to transform cells. The EWS/WT1 protein is such a fusion product, resulting from a t(11;22) chromosomal translocation in Desmoplastic Small Round Cell Tumor(DSRCT), where 265 amino acids from the amino terminus of Ewing's sarcoma protein(EWS) are fused to zinc fingers II-IV of WT1. The EWS gene is involved in several tumor-related chromosomal translocations that produce fusions with genes postulated to function as transcription factors. WT1 is a tumor suppressor gene expressed in the developing and adult urogenital system. WT1 encodes a zinc-finger transcription factor belonging to the EGR(early growth response) family of Cys₂-His₂ zinc finger proteins and is mutated in 5-15% of sporadic Wilms' Tumors. WT1 recognizes the GC-rich motif, 5'-GCGGGGGCG-3', as well as a (TCC)_(n) motif, albeit with different affinities, and can affect expression of a number of genes involved in the regulation of cell proliferation or differentiation. The t(11;22)(P13;q12) chromosomal translocation involved in DSRCT produces a chimeric protein containing the potential transcriptional activation domain of EWS fused to the DNA binding domain of WT1, suggesting that it may recognize similar DNA sequences as WT1. Since the DNA binding domains of WT1 and EWS/WT1 are structurally different, we have assessed the functional consequences of the EWS/WT1 fusion. In addition, we demonstrate that introduction of EWS/WT1(-KTS) into NIH3T3 cells causes tumorigenic transformation as determined by: formation of tramsformed foci on a monolayer of cells; anchorage-independent growth: and tumor formation in nude mice. EWS/WT1(+KTS) showed no transformation potential in these assays. These results indicate the oncogenic effect of the t(11;22) translocation is mediated by the EWS/WT1(-KTS) isoform and that fusion of the EWS amino terminal domain to the WT1 DNA binding domain produces a chimeric product showing a gain of function.