Project 4 - Oral Cell DNA Adducts and Urinary Biomarkers to Investigate Ethnic/Racial Differences in Lung Cancer Susceptibility
项目 4 - 利用口腔细胞 DNA 加合物和尿液生物标志物研究肺癌易感性的民族/种族差异
基本信息
- 批准号:9355615
- 负责人:
- 金额:$ 19.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-04-01 至
- 项目状态:未结题
- 来源:
- 关键词:1,3-Butadiene2-butenalAcetylcysteineAcroleinAffectAfrican AmericanAldehydesAlkylating AgentsAromatic Polycyclic HydrocarbonsBenzeneBiological MarkersCarcinogen exposureCarcinogenesis MechanismCarcinogensCellsCigaretteCollaborationsDNADNA AdductionDNA AdductsDNA DamageDNA Modification ProcessDNA RepairDataDinoprostoneDoseDrug Metabolic DetoxicationEthnic groupF2-IsoprostanesFormaldehydeGenerationsGenesGeneticIndividualInflammationJapanese AmericanLeadLinkLungMalignant NeoplasmsMalignant neoplasm of lungMass Spectrum AnalysisMeasurementMeasuresMetabolic ActivationMethodsMutationNative HawaiianNicotineNitrosaminesOne-Step dentin bonding systemOralOral mucous membrane structurePredispositionPrevention strategyProcessRecruitment ActivityResolutionRiskSamplingSmokerSmokingTechnologyTestingTimeTobaccoUrineadductbasecancer riskcarcinogenicitycaucasian Americancigarette smokingclinical biomarkerscohortethnic differencehigh riskinnovationinsightlung cancer preventionnever smokernon-smokeroxidative damageracial and ethnicracial differencetoxicanturinary
项目摘要
Project 4. Oral Cell DNA Adducts and Urinary Biomarkers to Investigate Ethnic/Racial Differences in
Lung Cancer Susceptibility.
ABSTRACT
Our ongoing studies demonstrate that carcinogen and toxicant doses account for some of the ethnic
differences in risk for lung cancer among smokers as observed in the Multiethnic Cohort. Carcinogen and
toxicant dose are only the first part of the risk paradigm for smoking-related lung cancer. DNA adduct formation
is the next critical step because DNA adducts lead to the multiple mutations that are found in smokers' lungs
and that cause miscoding, genetic instability, and cancer. Therefore, in this study, we will compare DNA adduct
formation in smokers from three ethnic groups with differing risks for lung cancer: Native Hawaiians (highest
risk), Whites (lower risk), and Japanese Americans (lowest risk). Three-hundred subjects will be recruited by
the Clinical and Biomarker Core. Oral cells, as a surrogate for lung cells, will be obtained for DNA adduct
measurements; urine samples will be collected for analysis of carcinogen and toxicant metabolites. Specific
DNA adducts as well as DNA adductomic signatures will be obtained from oral cells of each subject. Analysis
of the urine samples as well as those previously collected from never smokers will test the hypothesis that the
high lung cancer susceptibility of Native Hawaiians is partially due to endogenous generation of the toxicants
acrolein and crotonaldehyde, possibly due to inflammation and oxidative damage. Thus, our specific aims are:
1. Using high resolution mass spectrometry, quantify known DNA adducts in oral mucosa cells of 100
smokers from each ethnic group – Native Hawaiians, Whites, and Japanese Americans. DNA adducts of
tobacco-specific compounds, formaldehyde, and acrolein will be quantified.
2. Analyze the urine of 100 smokers and 100 non-smokers from each of these groups for mercapturic acids of
acrolein and crotonaldehyde, the F2-isoprostane 8-iso-PGF-2α, a biomarker of oxidative damage, and the
prostaglandin E2 metabolite PGEM, a biomarker of inflammation, as well as total nicotine equivalents and
total NNAL (smokers only). These data will provide critical information relevant to the high risk of Native
Hawaiians for lung cancer, and in relationship to the DNA adduct measurements of Specific Aim 1.
3. Use our newly developed high resolution mass spectrometric, high throughput DNA adductomic approach
to screen for known and unknown DNA adducts to identify a comprehensive DNA modification signature
derived from cigarette smoking.
a. Using a targeted DNA adductomic method we will screen for multiple DNA modifications
simultaneously. The adducts analyzed in Specific Aim 1 will be added to a list including
endogenous, 1,3-butadiene-derived (in collaboration with Project 3), aldehyde-derived and
nitrosamine or alkylating agent-derived DNA adducts. In parallel we will apply our DNA adductomic
method in an untargeted mode to investigate the presence of previously unknown DNA adducts.
The unknown adducts detected by the untargeted analysis will be included in the list of targeted
DNA adducts to ultimately obtain a sensitive method to assess overall DNA damage resulting from
cigarette smoking .
b. The list of DNA adducts created in Specific Aim 3a will be applied to investigate differences in the
DNA damage signature in selected samples analyzed in Specific Aim 1.
The results of this unique and innovative study will provide critical information relevant to the differing risks for
lung cancer among Native Hawaiians, Whites, and Japanese Americans. We expect generation of new
smoking-related DNA adduct signatures as well as important data on DNA adducts and urinary metabolites of
known carcinogens and toxicants. The results will provide a critical test of the relationship of DNA adducts and
certain urinary metabolites to lung cancer risk, thus possibly leading to new insights for lung cancer prevention
strategies.
项目4。口腔细胞DNA加合物和尿液生物标志物,以研究
肺癌易感性。
摘要
我们正在进行的研究表明,致癌物质和有毒物质的剂量占一些种族
在多种族队列中观察到的吸烟者患肺癌风险的差异。致癌物质和
有毒剂量只是吸烟相关肺癌风险范例的第一部分。DNA加合物形成
是下一个关键步骤,因为DNA加合物会导致吸烟者肺部发现的多种突变
导致错误编码,基因不稳定和癌症因此,在本研究中,我们将比较DNA加合物
来自三个具有不同肺癌风险的种族的吸烟者的形成:夏威夷土著人(最高
白人(风险较低)和日裔美国人(风险最低)。将招募300名受试者,
临床和生物标志物核心。将获得口腔细胞作为肺细胞的替代物用于DNA加合物
测量;将采集尿样用于分析致癌物和有毒代谢物。具体
将从每名受试者的口腔细胞中获得DNA加合物以及DNA内收体标记。分析
的尿液样本以及以前从从不吸烟者那里收集的样本将检验这一假设,
夏威夷原住民的高肺癌易感性部分是由于毒物的内源性产生
丙烯醛和巴豆醛,可能是由于炎症和氧化损伤。因此,我们的具体目标是:
1.使用高分辨率质谱,定量100个口腔粘膜细胞中已知的DNA加合物
每个种族的吸烟者-夏威夷土著人,白人和日裔美国人。DNA加合物
烟草特有的化合物、甲醛和丙烯醛将被定量。
2.分析每组100名吸烟者和100名非吸烟者的尿液中的巯基尿酸,
丙烯醛和巴豆醛,F2-异前列烷8-iso-PGF-2α,氧化损伤的生物标志物,以及
前列腺素E2代谢产物PGEM,炎症的生物标志物,以及总尼古丁当量,
总NNAL(仅吸烟者)。这些数据将提供与原发性高风险相关的关键信息
夏威夷人的肺癌,并与DNA加合物测量的具体目标1。
3.使用我们新开发的高分辨率质谱、高通量DNA内收体方法
筛选已知和未知的DNA加合物,以确定全面的DNA修饰特征
源于吸烟。
a.使用靶向DNA内收法,我们将筛选多种DNA修饰
同步具体目标1中分析的加合物将添加到列表中,包括
内源性、1,3-丁二烯衍生物(与项目3合作)、环糊精衍生物和
亚硝胺或烷化剂衍生的DNA加合物。与此同时,我们将应用我们的DNA内收切除术
方法以非靶向模式研究先前未知的DNA加合物的存在。
通过非靶向分析检测到的未知加合物将被包括在靶向加合物列表中。
DNA加合物,以最终获得一种敏感的方法来评估由DNA加合物引起的总体DNA损伤。
吸烟。
B.特定目标3a中创建的DNA加合物列表将用于研究
特定目标1中分析的选定样品中的DNA损伤特征。
这项独特的创新研究的结果将提供与不同风险相关的关键信息,
夏威夷原住民、白人和日裔美国人中的肺癌。我们期待新一代
吸烟相关的DNA加合物特征以及关于DNA加合物和尿代谢物的重要数据
已知的致癌物质和有毒物质。这些结果将为DNA加合物与DNA结合的关系提供一个重要的实验依据。
某些尿液代谢物与肺癌风险的关系,从而可能为肺癌预防带来新的见解
战略布局
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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{{ truncateString('STEPHEN S HECHT', 18)}}的其他基金
High resolution mass spectrometric profile analysis of carcinogen-DNA adducts in oral cells of cigarette smokers and squamous cell carcinoma of the head and neck
吸烟者口腔细胞和头颈部鳞状细胞癌中致癌物-DNA 加合物的高分辨率质谱分析
- 批准号:
10275874 - 财政年份:2021
- 资助金额:
$ 19.1万 - 项目类别:
High resolution mass spectrometric profile analysis of carcinogen-DNA adducts in oral cells of cigarette smokers and squamous cell carcinoma of the head and neck
吸烟者口腔细胞和头颈部鳞状细胞癌中致癌物-DNA 加合物的高分辨率质谱分析
- 批准号:
10693217 - 财政年份:2021
- 资助金额:
$ 19.1万 - 项目类别:
High resolution mass spectrometric profile analysis of carcinogen-DNA adducts in oral cells of cigarette smokers and squamous cell carcinoma of the head and neck
吸烟者口腔细胞和头颈部鳞状细胞癌中致癌物-DNA 加合物的高分辨率质谱分析
- 批准号:
10491887 - 财政年份:2021
- 资助金额:
$ 19.1万 - 项目类别:
Tobacco Constituent and Biomarker Assessment Core
烟草成分和生物标志物评估核心
- 批准号:
8310412 - 财政年份:2012
- 资助金额:
$ 19.1万 - 项目类别:
Mechanisms of Ethnic/Racial Differences in Lung Cancer Due to Cigarette Smoking
吸烟导致肺癌的民族/种族差异机制
- 批准号:
7765754 - 财政年份:2010
- 资助金额:
$ 19.1万 - 项目类别: