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

剖析 DNA 损伤修复缺陷在尤文肉瘤发病机制中的作用，以改善风险分层和治疗

基本信息

批准号：
10738078
负责人：
Riaz Gillani
金额：
$ 20.83万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-19 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10738078
关键词：
Adolescent Biological Biological Assay Biological Factors Biological Markers Biology Bone Tissue Cell Line Cells Child Clinical Trials Combined Modality Therapy Complex Computational Biology DNA Damage DNA Repair Data Set Development Disease EWSR1 gene Evaluation Ewings sarcoma Fibroblasts Foundations Gene Fusion Genetic Genetic Complementation Test Genetic Predisposition to Disease Genomic Instability Genomics Genotoxic Stress Germ-Line Mutation Goals Heterozygote In Vitro Inherited Investigation Knowledge Link Malignant Childhood Neoplasm Malignant Neoplasms Matched Case-Control Study Mediator Mentorship Mesenchymal Mesenchymal Stem Cells Mitomycin C Modeling Molecular Morbidity - disease rate Mutation Nonhomologous DNA End Joining Parents Pathogenesis Pathogenicity Patients Pattern Pharmacotherapy Phenotype Predisposition Process Recurrent disease Relapse Reporter Research Proposals Role Therapeutic Tissue-Specific Gene Expression Variant Work cancer predisposition childhood sarcoma clinically relevant cohort gene repair genomic signature homologous recombination improved insight loss of function novel novel strategies predicting response proband prognostic programs response risk prediction risk stratification risk variant screening skills soft tissue targeted agent treatment response tumor tumorigenesis

项目摘要

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.

项目概要尤文肉瘤是影响儿童和儿童的第二常见骨和软组织癌症全世界的青少年。这是一种侵袭性恶性肿瘤，需要多模式治疗，可显着改善预后转移性和复发性疾病的发病率和治愈率仍然很低。虽然尤文肉瘤是由 EWSR1-ETS 基因融合表征和驱动，促成这些简单的生物因素重排，以及在某些情况下称为染色体复合体的复杂重排，不太好- 特点。我发现FANCC和其他DNA损伤修复（DDR）中遗传的致病性变异相对于其他儿科肉瘤亚型，尤文肉瘤患者的基因特别丰富（Gillani 等人，AJHG 2022）。仍需开展大量工作来了解 DNA 损伤修复缺陷的机制有助于尤文肉瘤的发病机制。本研究计划的指导性假设是 DNA 损伤修复缺陷促进尤文肉瘤发病机制，表现为一种独特的模式易感种系变异和肿瘤基因组特征是肿瘤发生不可或缺的一部分，并且可以可用于更明智的风险分层和治疗。我们将应用计算和实验方法对患有以下疾病的患者的数据集进行测序尤文肉瘤和细胞系模型完成了这项研究计划。在具体目标 1 中，我们将剖析较大种系结构变异影响尤文肉瘤中 DDR 基因的附加贡献分析 301 名亲先证者三人组并评估种系结构变异的富集 1180 例与无癌对照组相关。在具体目标 2 中，我们将定义 FANCC 变体的表型在尤文肉瘤患者的种系中发现了这些变异，并将这些变异敲入间充质干细胞系中了解它们如何在存在基因毒性应激的情况下导致基因组不稳定。在具体目标 3 中，我们将获得基因组特征，以进一步了解 DNA 损伤过程尤因肉瘤肿瘤并将拷贝数特征与治疗反应特别相关复发。最后，我们将进行体外药物治疗研究，以证明特定拷贝的效用数字签名作为 DNA 损伤反应靶向剂敏感性的生物标志物。通过跨越种系和肿瘤的综合研究，我们打算推动新的研究了解 DNA 损伤如何在尤文肉瘤发病机制中发挥作用，这将是核心知识改善这种侵袭性儿科癌症的风险分层和治疗。此外，在扩展我们的对种系结构变异、杂合风险变异在癌症中的作用有更广泛的了解倾向和拷贝数签名作为临床相关的生物标志物，这项工作也将具有很高的与其他儿科癌症的相关性。