Mechanisms of cancer mutations

癌症突变机制

基本信息

  • 批准号:
    10563024
  • 负责人:
  • 金额:
    $ 48.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-12-01 至 2027-11-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY: Cancer genome sequencing has identified thousands of somatic mutations in different types of human cancer. These mutations provide a valuable source of information as to the potential mutagenic events that have occurred and created the mutations, sometimes decades before the tumor develops. For certain cancers, convincing links between an exposure and cancer mutations have been established, best exemplified by typical sunlight-induced mutations (C to T mutations at dipyrimidine sequences) that are prevalent in melanoma and in non-melanoma skin cancers and by smoking- related G to T transversion mutations that are common in lung cancers from smokers but not nonsmokers. The types and frequencies of mutations in different tumor types is called the mutational signature. Several signatures also have a characteristic DNA strand bias related to, for example, the direction of transcription. In several human cancers, there are unusual and characteristic mutational signatures of unknown origin. These signatures are thought to arise from specific DNA damage, defective DNA repair or from endogenous processes. We hypothesize that we can identify and recreate mutagenic signatures using DNA damage mapping, a procedure in which we determine DNA lesions of a specific type at all sequence positions of the human genome, combined with mutational analysis, with the goal of assigning mutational signatures to etiological agents relevant for specific human cancers. One key challenge in this field is method development. The method needs to be sufficiently sensitive to detect rare DNA lesions and must be capable of doing so at all positions of the genome. We have developed such a method, which we named circle-damage-sequencing (CD-seq). We propose three Specific Aims. In the first Aim, we will use our new method to characterize and map reactive aldehyde-derived DNA adducts that we hypothesize play a crucial role in liver cancer. In the second Aim, we will test the hypothesis that 8-oxo-dG incorporated from the nucleotide pool is responsible for sequence-specific A to C transversion mutations observed as a dominant mutation type in human esophageal adenocarcinomas. The last Aim will have the goal of understanding the mechanisms of targeted mutagenesis by tobacco smoke carcinogens of the PAH class and how this targeting relates to lung and oral squamous cell carcinomas in tobacco users. Our DNA damage studies will be complemented by mutation assays to confirm that the relevant pathways induce the expected types of mutations. Our proposed work will provide mechanistic insights into the potential origin of human cancer mutations. We anticipate that our methods will aid in many future studies of DNA damage and repair and will help identify other mutagenic mechanisms.
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)

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Gerd P Pfeifer其他文献

Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers
吸烟相关癌症中的烟草烟雾致癌物质、DNA 损伤和 p53 突变
  • DOI:
    10.1038/sj.onc.1205803
  • 发表时间:
    2002-10-15
  • 期刊:
  • 影响因子:
    7.300
  • 作者:
    Gerd P Pfeifer;Mikhail F Denissenko;Magali Olivier;Natalia Tretyakova;Stephen S Hecht;Pierre Hainaut
  • 通讯作者:
    Pierre Hainaut

Gerd P Pfeifer的其他文献

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{{ truncateString('Gerd P Pfeifer', 18)}}的其他基金

5-methylcytosine oxidation in development and disease
发育和疾病中的 5-甲基胞嘧啶氧化
  • 批准号:
    10405494
  • 财政年份:
    2021
  • 资助金额:
    $ 48.25万
  • 项目类别:
5-methylcytosine oxidation in development and disease
发育和疾病中的 5-甲基胞嘧啶氧化
  • 批准号:
    10183599
  • 财政年份:
    2021
  • 资助金额:
    $ 48.25万
  • 项目类别:
5-methylcytosine oxidation in development and disease
发育和疾病中的 5-甲基胞嘧啶氧化
  • 批准号:
    10590717
  • 财政年份:
    2021
  • 资助金额:
    $ 48.25万
  • 项目类别:
DNA hypermethylation in lung tumors
肺部肿瘤中的 DNA 高甲基化
  • 批准号:
    10222620
  • 财政年份:
    2019
  • 资助金额:
    $ 48.25万
  • 项目类别:
DNA hypermethylation in lung tumors
肺部肿瘤中的 DNA 高甲基化
  • 批准号:
    10022487
  • 财政年份:
    2019
  • 资助金额:
    $ 48.25万
  • 项目类别:
DNA hypermethylation in lung tumors
肺部肿瘤中的 DNA 高甲基化
  • 批准号:
    10472533
  • 财政年份:
    2019
  • 资助金额:
    $ 48.25万
  • 项目类别:
DNA hypermethylation in lung tumors
肺部肿瘤中的 DNA 高甲基化
  • 批准号:
    10683173
  • 财政年份:
    2019
  • 资助金额:
    $ 48.25万
  • 项目类别:
5-hydroxymethylcytosine in human cancer
5-羟甲基胞嘧啶在人类癌症中的作用
  • 批准号:
    8446395
  • 财政年份:
    2012
  • 资助金额:
    $ 48.25万
  • 项目类别:
5-hydroxymethylcytosine in human cancer
5-羟甲基胞嘧啶在人类癌症中的作用
  • 批准号:
    8990561
  • 财政年份:
    2012
  • 资助金额:
    $ 48.25万
  • 项目类别:
5-hydroxymethylcytosine in human cancer
5-羟甲基胞嘧啶在人类癌症中的作用
  • 批准号:
    8292990
  • 财政年份:
    2012
  • 资助金额:
    $ 48.25万
  • 项目类别:

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腺嘌呤核苷酸转位酶在慢性阻塞性肺病(COPD)线粒体功能相关衰老中的作用
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  • 财政年份:
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  • 批准号:
    10794933
  • 财政年份:
    2022
  • 资助金额:
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使用 FRET 开发 miRNA 和腺嘌呤甲基转移酶的诺贝尔检测方法
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健康老龄化和阿尔茨海默病脑细胞 DNA 腺嘌呤甲基化的批判性评估
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胎盘滋养层发育中 N6-腺嘌呤 DNA 甲基化
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胎盘滋养层发育中 N6-腺嘌呤 DNA 甲基化
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  • 财政年份:
    2020
  • 资助金额:
    $ 48.25万
  • 项目类别:
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胎盘滋养层发育中 N6-腺嘌呤 DNA 甲基化
  • 批准号:
    10226235
  • 财政年份:
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  • 资助金额:
    $ 48.25万
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胎盘滋养层发育中 N6-腺嘌呤 DNA 甲基化
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