Oncogenic pathway-induced fragile sites: a new paradigm for understanding genome instability in cancer

致癌途径诱导的脆弱位点:了解癌症基因组不稳定性的新范例

基本信息

项目摘要

ABSTRACT One of the grand challenges in cancer research is the vast heterogeneity in responsiveness to treatment for different cancer types. We have made great strides in treating some cancers, while the prognosis for others remains dismal. Large scale whole genome sequence (WGS) analyses have identified “breakpoint signatures” of different cancer types that presumably reflect heterogeneity in their underlying disrupted pathways but, drug- gable targets have emerged only in cases where the breaks create oncogenic fusion proteins. The ability to predict disrupted pathways using WGS would be highly impactful for cancer diagnosis and treatment. Chromo- some fragile sites (FSs) manifest as gaps and breaks in metaphase chromosomes when cultured cells experi- ence replication stress. However, many FSs are not cancer-type specific and many breakpoint hotspots in cancer are not known FSs, which has severely limited the impact of the FS field. Since cultured cells offer the potential to prospectively dissect mechanisms initiating chromosome breaks and to track their expansion into complex structural variation, there is a critical need to make these in vitro systems more cancer relevant. Our longterm goal is to establish a sustained research strategy that can predict which known pathways are disrupted in a given cancer type from their breakpoint patterns. The overall objective of this proposal is to reveal mechanisms by which perturbation of cancer-relevant cellular pathways produce pathway-specific patterns of FSs in cell culture and determine whether those patterns can be identified in cancers. Our central hypothesis is that the power of in vitro systems to dissect mechanisms leading to cancer breakpoint signatures will become evident only when shifted away from chemically-induced FSs towards FSs induced by perturbing known cancer-relevant pathways. We have shown that overexpression of different oncogenes leads to oncogene-specific spectra of FSs and pre- liminary data suggest some of the mechanisms by which this occurs. Our rationale is that understanding cancer- relevant mechanisms that specify FSs will fill the gap in linking in vitro FSs to cancer breakpoints. This would be a major step toward a strategy to predict disrupted pathways from cancer WGS data, thereby suggesting treat- ments for previously intractable cancers. Aim1 will use high throughput/resolution replication and Oligopaints assays to identify downstream mechanisms distinguishing which of many sites of oncogene-induced replication delay manifest as FSs. Aim2 will elucidate upstream mechanisms causing replication delays and FS at specific sites. Aim3 will map FSs at unprededented resolution and mine tumor sequencing databases for signatures that match those of oncogene-specific FSs. This contribution will be significant because the ability to identify affected pathways solely from breakpoint signatures would expose tumor-specific vulnerabilities for precision cancer medicine. The proposed research is innovative because it will rejuvenate the impact of FS research, closing the gap between in vitro systems and in vivo cancers while leveraging novel technologies to manipulate cells, map their signatures of genome instability and match them to cancer breakpoint signatures.
摘要

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 }}

David M Gilbert其他文献

Intranuclear changes in cancer cells
  • DOI:
    10.1186/gb-2007-8-8-312
  • 发表时间:
    2007-01-01
  • 期刊:
  • 影响因子:
    9.400
  • 作者:
    David M Gilbert;Daniele Zink
  • 通讯作者:
    Daniele Zink
Roles of Rif1 in regulation of DNA replication, transcription and DNA repair
Rif1 在 DNA 复制、转录和 DNA 修复调节中的作用
  • DOI:
  • 发表时间:
    2015
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Satoshi Yamazaki;Jiao Sima;Yumeka Matsushima;Kenji Moriyama;Naoko Yoshizawa;Sara Buonomo;David M Gilbert;Hisao Masai
  • 通讯作者:
    Hisao Masai

David M Gilbert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 }}

{{ truncateString('David M Gilbert', 18)}}的其他基金

Mapping the 3D architecture of native human replisomes
绘制天然人类复制体的 3D 架构
  • 批准号:
    10461210
  • 财政年份:
    2019
  • 资助金额:
    $ 50.49万
  • 项目类别:
Mapping the 3D architecture of native human replisomes
绘制天然人类复制体的 3D 架构
  • 批准号:
    10400294
  • 财政年份:
    2019
  • 资助金额:
    $ 50.49万
  • 项目类别:
Additional Tool Development or Data Generation
额外的工具开发或数据生成
  • 批准号:
    9020717
  • 财政年份:
    2015
  • 资助金额:
    $ 50.49万
  • 项目类别:
Replication domain organization during hESC differentiation
hESC 分化过程中的复制域组织
  • 批准号:
    8641824
  • 财政年份:
    2014
  • 资助金额:
    $ 50.49万
  • 项目类别:
Replication Profiling as a Diagnostic Tool in B-cell Acute Lymphoblastic Leukemia
复制分析作为 B 细胞急性淋巴细胞白血病的诊断工具
  • 批准号:
    8594233
  • 财政年份:
    2012
  • 资助金额:
    $ 50.49万
  • 项目类别:
Replication Profiling as a Diagnostic Tool in B-cell Acute Lymphoblastic Leukemia
复制分析作为 B 细胞急性淋巴细胞白血病的诊断工具
  • 批准号:
    8445645
  • 财政年份:
    2012
  • 资助金额:
    $ 50.49万
  • 项目类别:
Replication Domain Organization during hESC Differentiation
hESC 分化期间的复制域组织
  • 批准号:
    8382720
  • 财政年份:
    2012
  • 资助金额:
    $ 50.49万
  • 项目类别:
Genome Plasticity during ES Cell Differentiation to Neural Lineages
ES 细胞分化为神经谱系期间的基因组可塑性
  • 批准号:
    7910975
  • 财政年份:
    2009
  • 资助金额:
    $ 50.49万
  • 项目类别:
cis-Acting Elements Regulating Developmental Control of Replication Timing
调节复制时间发育控制的顺式作用元件
  • 批准号:
    8238959
  • 财政年份:
    2007
  • 资助金额:
    $ 50.49万
  • 项目类别:
cis-Acting Elements Regulating Developmental Control of Replication Timing
调节复制时间发育控制的顺式作用元件
  • 批准号:
    9296144
  • 财政年份:
    2007
  • 资助金额:
    $ 50.49万
  • 项目类别:

相似海外基金

RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    $ 50.49万
  • 项目类别:
    Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    $ 50.49万
  • 项目类别:
    Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    $ 50.49万
  • 项目类别:
    Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    $ 50.49万
  • 项目类别:
    Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    $ 50.49万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    $ 50.49万
  • 项目类别:
    Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    $ 50.49万
  • 项目类别:
    Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
  • 批准号:
    2301846
  • 财政年份:
    2023
  • 资助金额:
    $ 50.49万
  • 项目类别:
    Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    $ 50.49万
  • 项目类别:
    Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
  • 批准号:
    23K16076
  • 财政年份:
    2023
  • 资助金额:
    $ 50.49万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了