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
- 来源:
- 关键词:8-oxo-dGTPAdenineAldehydesAromatic Polycyclic HydrocarbonsBase SequenceCarcinogensCell Culture SystemCharacteristicsComplementCytosineDNADNA AdductionDNA AdductsDNA DamageDNA MethylationDNA RepairDNA SequenceDNA lesionDependenceEnvironmental ExposureEnzymesEsophageal AdenocarcinomaEsophagusEtiologyEventFelis catusFrequenciesFutureGenesGenetic TranscriptionGenomeGeographyGoalsGuanineHumanHuman GenomeInduced MutationInflammationKnowledgeLesionLinkLipid PeroxidationLungMalignant NeoplasmsMalignant neoplasm of esophagusMalignant neoplasm of liverMalignant neoplasm of lungMapsMeasuresMethodologyMethodsMutagenesisMutateMutationMutation AnalysisNamesNucleotidesOxidative StressPathologicPathway interactionsPatternPlayPositioning AttributeProceduresProcessRare LesionResolutionRoleScienceSkin CarcinomaSmokerSmokingSomatic MutationSourceSpecificityTechnologyTestingTissuesTobaccoTobacco smokeTobacco-Associated CarcinogenTobacco-Related CarcinomaWorkadductcancer genomecancer typedominant genetic mutationenvironment related cancergenome sequencinggenome-wideinsightmelanomamethod developmentmouth squamous cell carcinomamutation assaysunlight-inducedtobacco usertransversion mutationtumor
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:
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