Characterization of Ewing's sarcoma susceptibility loci

尤文斯肉瘤(ES)是儿童第二常见的骨癌类型，转移率高。自1921年詹姆斯·尤因首次描述它以来，其确切的起源细胞和肿瘤发生机制仍然难以捉摸。因此，目前缺乏合适的动物模型，这阻碍了新疗法的发展。在遗传学上，所有ES的特征是融合癌基因，涉及EWS和FLI1基因或ETS转录因子家族的另一个成员的染色体易位。尽管EWS/FLI1在ES中作为癌基因发挥作用，但它对大多数细胞都是有毒的。这一观察表明，可能存在额外的潜在基因改变，只存在于少数人中，这是为充分表达EWS/FLI1创造允许的环境，从而建立ES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可能含有这些允许因子的基因组易感区域。该项目旨在确定三个基因组ES易感区域的功能特征，以确定有助于ES发育的真正致病多态。对这些致病突变的了解可能是识别真正的ES起源细胞和设计适当的ES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.