Dissecting the role of DNA damage repair deficiency in Ewing sarcoma pathogenesis for improved risk stratification and treatment

点击翻译按钮获取中文摘要

PROJECT SUMMARY Ewing sarcoma is the second most common bone and soft tissue cancer impacting children and adolescents worldwide. It is an aggressive malignancy requiring multimodal treatment that confers significant morbidity, and cure rates for metastatic and relapsed disease remain poor. While Ewing sarcoma is characterized and driven by EWSR1-ETS gene fusions, the biological factors contributing to these simple rearrangements, and complex rearrangements known as chromoplexy in a subset of cases, are not well- characterized. I found that inherited pathogenic variants in FANCC and other DNA damage repair (DDR) genes are uniquely enriched among patients with Ewing sarcoma relative to other pediatric sarcoma subtypes (Gillani et al., AJHG 2022). Much work is still needed to understand how DNA damage repair deficiency contributes to Ewing sarcoma pathogenesis. The guiding hypothesis of this research proposal is that DNA damage repair deficiency promotes Ewing sarcoma pathogenesis, manifesting as a unique pattern of predisposing germline variants and tumor genomic features that are integral to oncogenesis and can be utilized for more informed risk stratification and treatment. We will apply computational and experimental approaches to sequencing datasets from patients with Ewing sarcoma and cell line models to complete this research proposal. In Specific Aim 1, we will dissect the additive contribution of larger germline structural variants impacting DDR genes in Ewing sarcoma by analyzing a cohort of 301 parent-proband trios and evaluating the enrichment of germline structural variants in 1180 cases relative to cancer-free controls. In Specific Aim 2, we will define the phenotype of FANCC variants seen in the germline of Ewing sarcoma patients and knock these variants into mesenchymal stem cell lines to understand how they contribute to genomic instability in the presence of genotoxic stress. In Specific Aim 3, we will derive genomic signatures to gain additional insight into the DNA damage processes that are operant in Ewing sarcoma tumors and associate copy number signatures specifically with treatment response and relapse. Finally, we will conduct in-vitro drug treatment studies to demonstrate the utility of specific copy number signatures as biomarkers of sensitivity to DNA damage response targeting agents. Through integrative investigations spanning the germline and tumor, we intend to drive new understanding of how DNA damage operates in Ewing sarcoma pathogenesis, knowledge that will be central to improved risk stratification and treatment of this aggressive pediatric cancer. Moreover, in extending our broader understanding about germline structural variants, the role of heterozygous risk variants in cancer predisposition, and copy number signatures as clinically relevant biomarkers, this work will also have high relevance to other pediatric cancers.