Characterization of Ewing's sarcoma susceptibility loci

• Applicant: Professor Thomas Grünewald, Ph.D.
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2012 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 218246939

Ewings sarcoma (ES) is the second most common type of bone cancer in children and features high rates of metastasis. Since its initial description by James Ewing in 1921, its precise cell of origin and its mechanisms of tumorigenesis remain elusive. Accordingly, there is a current lack of adequate animal models, which hampers the development of novel therapies. Genetically, all ES are characterized by fusion oncogenes resulting from chromosomal translocations involving the EWS and FLI1 gene or another member of the ETS family of transcription factors. Despite its action as an oncogene in ES, EWS/FLI1 is toxic to most cells. This observation suggests that additional underlying genetic alterations might exist, present only in a minority of individuals, which are necessary to create a permissive milieu for full EWS/FLI1 expression and thus ES establishment. In support of this notion, a recent genome-wide association study identified three genomic susceptibility regions possibly harboring these permissive factors. This project aims to functionally characterize the three genomic ES susceptibility regions to identify truly causative polymorphisms that contribute to ES development. The knowledge about these causative mutations is likely to be key for the identification of the real ES cell of origin and to engineer proper ES animal models to advance research for novel therapies.

• DFG Programme: Research Fellowships
• International Connection: France
• Host: Professor Dr. Olivier Delattre