Characterization of Ewing's sarcoma susceptibility loci

尤因肉瘤（ES）是儿童中第二常见的骨癌类型，具有高转移率。自1921年由詹姆斯·尤因（James Ewing）首次描述以来，其确切的细胞起源和肿瘤发生机制一直难以捉摸。因此，目前缺乏足够的动物模型，这阻碍了新疗法的发展。从遗传学上讲，所有ES都具有由染色体易位引起的融合癌基因的特征，涉及EWS和FLI1基因或ETS转录因子家族的另一个成员。尽管EWS/FLI1在ES中是致癌基因，但它对大多数细胞是有毒的。这一观察结果表明，额外的潜在遗传改变可能存在，仅存在于少数个体中，这是为EWS/FLI1的完全表达和ES的建立创造一个允许环境所必需的。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性区域可能包含这些允许因子。该项目旨在功能表征三个基因组ES易感性区域，以确定真正导致ES发展的致病多态性。了解这些致病突变可能是鉴定真正的胚胎干细胞起源和设计适当的胚胎干细胞动物模型以推进新疗法研究的关键。

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.