Characterization of Ewing's sarcoma susceptibility loci

尤文肉瘤易感位点的特征

• 批准号: 218246939
• 负责人: Professor Dr. Thomas Grünewald, Ph.D.
• 金额: --
• 依托单位: INSERM Unit 830 "Genetics and Biology of Cancers"
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/218246939?language=en
• 关键词: Characterization; Ewing; sarcoma; susceptibility; loci

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.

尤文氏肉瘤（ES）是儿童第二常见的骨癌类型，具有高转移率。自1921年James Ewing首次描述以来，其确切的起源细胞及其肿瘤发生机制仍然难以捉摸。因此，目前缺乏足够的动物模型，这阻碍了新疗法的开发。在遗传学上，所有ES的特征在于融合癌基因，其由涉及EWS和FLI 1基因或ETS家族转录因子的另一成员的染色体易位引起。尽管EWS/FLI 1在ES中作为致癌基因发挥作用，但它对大多数细胞都有毒性。这一观察结果表明，可能存在额外的潜在遗传改变，仅存在于少数个体中，这对于创造一个允许EWS/FLI 1完全表达的环境以及ES建立是必要的。为了支持这一观点，最近的一项全基因组关联研究确定了三个基因组易感区域可能含有这些允许因子。该项目旨在从功能上表征三个基因组ES易感区域，以确定真正的致病多态性，有助于ES的发展。这些致病突变的知识可能是关键的真实的ES细胞的起源和工程师适当的ES动物模型，以推进新的治疗研究。