Gene-tobacco carcinogen interactions and lung cancer risk - a novel approach for precision cancer prevention
基因-烟草致癌物相互作用和肺癌风险——精准癌症预防的新方法
基本信息
- 批准号:10581340
- 负责人:
- 金额:$ 66.8万
- 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:2022-12-16 至 2027-11-30
- 项目状态:未结题
- 来源:
- 关键词:4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone7alpha hydroxylaseAllelesAsianBiological MarkersBlack raceBlood specimenCancer BurdenCancer EtiologyCarcinogensCellsCessation of lifeChemopreventive AgentChineseCohort StudiesCommunitiesComplexCopy Number PolymorphismCytochrome P450CytosolDataDevelopmentDrug Metabolic DetoxicationEnzymesExhibitsGenesGenetic MarkersGenetic PolymorphismGenetic VariationGenotypeGlucuronidesGlucuronosyltransferaseGoalsHealthHumanIsomerismLiverLungMalignant neoplasm of lungMediatingMetabolicMetabolismMicrosomesNicotineNitrosaminesOxidoreductasePathway interactionsPatternPhenotypePlayPopulationPredispositionPrevention strategyProspective cohortProspective, cohort studyProtein IsoformsRiskRoleSNP genotypingSingaporeSmokerSmokingTissuesTobaccoTobacco smokeTobacco-Associated CarcinogenUrineValidationVariantWomen&aposs Healthcancer riskcarcinogenesiscarcinogenicitycigarette smokingcohortcost effectiveenantiomergenetic variantgenome wide association studygenome-widehigh riskimprovedinsightlung cancer preventionlung cancer screeninglung carcinogenesislung developmentmortalitynovelnovel strategiesphenotypic biomarkerprecision cancer preventionprospectiveprotective pathwayrecruitsample collectionscreeningsmoking cessationtargeted sequencingurinary
项目摘要
The tobacco-specific nitrosamine (TSNA), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is considered
a major contributor to the induction of lung cancer in smokers. The metabolism of NNK is complex with its
carcinogenic effects likely via the formation of its major pro-carcinogenic metabolite, 4-(methylnitrosamino)-1-
(3-pyridyl)-1-butanol (NNAL). Two enantiomers of NNAL are formed: (R)- and (S)-NNAL, both of which are
extensively detoxified by glucuronidation in humans. Our novel preliminary data demonstrate a strong and
statistically significant inverse association between the ratio of urinary (R)-NNAL-glucuronide (Gluc)/(S)-NNAL-
Gluc and lung cancer risk in two independent prospective cohort studies. Furthermore, smokers homozygous
for the deletion polymorphism of the major NNAL-glucuronidating enzyme, UGT2B17, had a significant 3-fold
higher risk for lung cancer than those with at least one functional UGT2B17 allele in both cohorts. These data
strongly support our hypothesis that (R)-NNAL plays a key role in tobacco-induced lung carcinogenesis and
suggests that we have identified novel important phenotypic and genetic markers of lung cancer risk. The goal
of this proposal is to evaluate the importance of NNAL enantiomers and glucuronides in lung cancer
carcinogenesis, and to elucidate novel phenotypic and genetic markers of NNAL formation and elimination
pathways and lung cancer risk in multiple populations. Our goals are to prospectively evaluate whether the
levels or ratios of specific urinary NNAL isomers or glucuronides are associated with lung cancer risk in: (1)
Chinese smokers from three cohort studies from Shanghai and Singapore, and (2) White and Black smokers
from the Southern Community Cohort Study, and to subsequently screen and validate genetic variants
associated with the variability in NNAL enantiomer and glucuronide formation. These studies should provide
crucial insight for understanding variability and establishing phenotypes and genotypes important in lung
cancer risk and will assist in identifying smokers at high risk for lung cancer for the development of
chemopreventive strategies targeting the NNK metabolism pathway.
本文研究了烟草特有的亚硝胺(TSNA)4-(甲基亚硝胺基)-1-(3-吡啶基)-1-丁酮(NNK)
是诱发吸烟者肺癌的主要因素。NNK的代谢是复杂的,
致癌作用可能是通过形成其主要的促致癌代谢产物4-(甲基亚硝胺)-1-
(3-吡啶基)-1-丁醇(NNAL)。形成NNAL的两种对映异构体:(R)-和(S)-NNAL,两者均为
在人体内通过葡萄糖醛酸化广泛解毒。我们新的初步数据表明,
尿(R)-NNAL-葡萄糖醛酸苷(Gluc)/(S)-NNAL-葡萄糖醛酸苷比值之间呈统计学显著负相关。
两项独立前瞻性队列研究中Gluc与肺癌风险的关系。此外,吸烟者纯合子
对于主要的NNAL-葡萄糖醛酸化酶UGT 2B 17的缺失多态性,
在两个队列中,肺癌的风险高于至少有一个功能性UGT 2B 17等位基因的患者。这些数据
强烈支持我们的假设,即(R)-NNAL在烟草诱导的肺癌发生中发挥关键作用,
表明我们已经确定了新的重要的肺癌风险表型和遗传标记。目标
本研究的目的是评估NNAL对映体和葡萄糖醛酸苷在肺癌中的重要性
致癌作用,并阐明NNAL形成和消除的新表型和遗传标记
多个人群中的肺癌风险。我们的目标是前瞻性地评估
特定尿NNAL异构体或葡萄糖醛酸苷的水平或比率与肺癌风险相关:(1)
来自上海和新加坡3项队列研究的中国吸烟者,以及(2)白色和黑人吸烟者
从南部社区队列研究,并随后筛选和验证遗传变异
与NNAL对映体和葡糖苷酸形成的变异性相关。这些研究将提供
对于了解变异性和建立肺重要的表型和基因型至关重要的见解
癌症的风险,并将有助于确定吸烟者在肺癌的高风险,
靶向NNK代谢途径的化学预防策略。
项目成果
期刊论文数量(0)
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Philip Lazarus其他文献
Philip Lazarus的其他文献
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{{ truncateString('Philip Lazarus', 18)}}的其他基金
The UGT2A and 3A metabolizing enzymes and tobacco-related cancer risk
UGT2A 和 3A 代谢酶与烟草相关癌症风险
- 批准号:
9131748 - 财政年份:2015
- 资助金额:
$ 66.8万 - 项目类别:
The UGT2A and 3A metabolizing enzymes and tobacco-related cancer risk
UGT2A 和 3A 代谢酶与烟草相关癌症风险
- 批准号:
9221216 - 财政年份:2015
- 资助金额:
$ 66.8万 - 项目类别:
The UGT2A and 3A metabolizing enzymes and tobacco-related cancer risk
UGT2A 和 3A 代谢酶与烟草相关癌症风险
- 批准号:
9278174 - 财政年份:2015
- 资助金额:
$ 66.8万 - 项目类别:
Role of pharmacogenetics on exemestane metabolism and toxicity
药物遗传学对依西美坦代谢和毒性的作用
- 批准号:
8727490 - 财政年份:2012
- 资助金额:
$ 66.8万 - 项目类别:
Role of pharmacogenetics on exemestane metabolism and toxicity
药物遗传学对依西美坦代谢和毒性的作用
- 批准号:
8915094 - 财政年份:2012
- 资助金额:
$ 66.8万 - 项目类别:
Role of pharmacogenetics on exemestane metabolism and toxicity
药物遗传学对依西美坦代谢和毒性的作用
- 批准号:
8372081 - 财政年份:2012
- 资助金额:
$ 66.8万 - 项目类别:
Role of pharmacogenetics on exemestane metabolism and toxicity
药物遗传学对依西美坦代谢和毒性的作用
- 批准号:
8527745 - 财政年份:2012
- 资助金额:
$ 66.8万 - 项目类别:
UDP-GLUCURONOSYLTRANSFERASE GENOTYPE AND CANCER RISK
UDP-葡萄糖醛酸基转移酶基因型和癌症风险
- 批准号:
7265009 - 财政年份:2007
- 资助金额:
$ 66.8万 - 项目类别:
UDP-GLUCURONOSYLTRANSFERASE GENOTYPE AND CANCER RISK
UDP-葡萄糖醛酸基转移酶基因型和癌症风险
- 批准号:
7612146 - 财政年份:2007
- 资助金额:
$ 66.8万 - 项目类别:
UDP-GLUCURONOSYLTRANSFERASE GENOTYPE AND CANCER RISK
UDP-葡萄糖醛酸基转移酶基因型和癌症风险
- 批准号:
8064730 - 财政年份:2007
- 资助金额:
$ 66.8万 - 项目类别:
相似海外基金
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项目 2 - 4-(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮 (NNK) α-羟基葡萄糖醛酸、代谢分析和激活
- 批准号:
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The roles of different cytochrome P450 isozymes and prostagladin H synthase in pulmonary microsomal 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) biotransformation
不同细胞色素P450同工酶和前列腺素H合酶在肺微粒体4-(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮(NNK)生物转化中的作用
- 批准号:
303377-2004 - 财政年份:2004
- 资助金额:
$ 66.8万 - 项目类别:
Postgraduate Scholarships - Master's
Project 2 - 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) α-Hydroxy Glucuronides, Metabolic Profiling and Activation
项目 2 - 4-(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮 (NNK) α-羟基葡萄糖醛酸、代谢分析和激活
- 批准号:
9769641 - 财政年份:
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