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:
  • 金额:
    $ 20.83万
  • 依托单位:
  • 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

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.
项目总结

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Riaz Gillani其他文献

Riaz Gillani的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

相似海外基金

NSF/BIO-DFG: Biological Fe-S intermediates in the synthesis of nitrogenase metalloclusters
NSF/BIO-DFG:固氮酶金属簇合成中的生物 Fe-S 中间体
  • 批准号:
    2335999
  • 财政年份:
    2024
  • 资助金额:
    $ 20.83万
  • 项目类别:
    Standard Grant
Collaborative Research: Conference: Large Language Models for Biological Discoveries (LLMs4Bio)
合作研究:会议:生物发现的大型语言模型 (LLMs4Bio)
  • 批准号:
    2411529
  • 财政年份:
    2024
  • 资助金额:
    $ 20.83万
  • 项目类别:
    Standard Grant
Collaborative Research: Conference: Large Language Models for Biological Discoveries (LLMs4Bio)
合作研究:会议:生物发现的大型语言模型 (LLMs4Bio)
  • 批准号:
    2411530
  • 财政年份:
    2024
  • 资助金额:
    $ 20.83万
  • 项目类别:
    Standard Grant
Collaborative Research: NSF-ANR MCB/PHY: Probing Heterogeneity of Biological Systems by Force Spectroscopy
合作研究:NSF-ANR MCB/PHY:通过力谱探测生物系统的异质性
  • 批准号:
    2412551
  • 财政年份:
    2024
  • 资助金额:
    $ 20.83万
  • 项目类别:
    Standard Grant
Elucidating mechanisms of biological hydrogen conversion through model metalloenzymes
通过模型金属酶阐明生物氢转化机制
  • 批准号:
    2419343
  • 财政年份:
    2024
  • 资助金额:
    $ 20.83万
  • 项目类别:
    Standard Grant
Collaborative Research: The Interplay of Water Condensation and Fungal Growth on Biological Surfaces
合作研究:水凝结与生物表面真菌生长的相互作用
  • 批准号:
    2401507
  • 财政年份:
    2024
  • 资助金额:
    $ 20.83万
  • 项目类别:
    Standard Grant
DESIGN: Driving Culture Change in a Federation of Biological Societies via Cohort-Based Early-Career Leaders
设计:通过基于队列的早期职业领袖推动生物协会联盟的文化变革
  • 批准号:
    2334679
  • 财政年份:
    2024
  • 资助金额:
    $ 20.83万
  • 项目类别:
    Standard Grant
REU Site: Modeling the Dynamics of Biological Systems
REU 网站:生物系统动力学建模
  • 批准号:
    2243955
  • 财政年份:
    2024
  • 资助金额:
    $ 20.83万
  • 项目类别:
    Standard Grant
Defining the biological boundaries to sustain extant life on Mars
定义维持火星现存生命的生物边界
  • 批准号:
    DP240102658
  • 财政年份:
    2024
  • 资助金额:
    $ 20.83万
  • 项目类别:
    Discovery Projects
Advanced Multiscale Biological Imaging using European Infrastructures
利用欧洲基础设施进行先进的多尺度生物成像
  • 批准号:
    EP/Y036654/1
  • 财政年份:
    2024
  • 资助金额:
    $ 20.83万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了