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：
Philip Lazarus
金额：
$ 66.8万
依托单位：
WASHINGTON STATE UNIVERSITY
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：
https://reporter.nih.gov/project-details/10581340
关键词：
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone 7alpha hydroxylase Alleles Asian Biological Markers Black race Blood specimen Cancer Burden Cancer Etiology Carcinogens Cells Cessation of life Chemopreventive Agent Chinese Cohort Studies Communities Complex Copy Number Polymorphism Cytochrome P450 Cytosol Data Development Drug Metabolic Detoxication Enzymes Exhibits Genes Genetic Markers Genetic Polymorphism Genetic Variation Genotype Glucuronides Glucuronosyltransferase Goals Health Human Isomerism Liver Lung Malignant neoplasm of lung Mediating Metabolic Metabolism Microsomes Nicotine Nitrosamines Oxidoreductase Pathway interactions Pattern Phenotype Play Population Predisposition Prevention strategy Prospective cohort Prospective, cohort study Protein Isoforms Risk Role SNP genotyping Singapore Smoker Smoking Tissues Tobacco Tobacco smoke Tobacco-Associated Carcinogen Urine Validation Variant Women&apos s Health cancer risk carcinogenesis carcinogenicity cigarette smoking cohort cost effective enantiomer genetic variant genome wide association study genome-wide high risk improved insight lung cancer prevention lung cancer screening lung carcinogenesis lung development mortality novel novel strategies phenotypic biomarker precision cancer prevention prospective protective pathway recruit sample collection screening smoking cessation targeted sequencing urinary

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.

烟草特有的亚硝胺 (TSNA)，4-(甲基亚硝胺)-1-(3-吡啶基)-1-丁酮 (NNK)，被认为是是吸烟者诱发肺癌的主要因素。 NNK 的代谢非常复杂致癌作用可能是通过其主要致癌代谢物 4-(甲基亚硝基氨基)-1- 的形成而产生的 (3-吡啶基)-1-丁醇(NNAL)。 NNAL 形成两种对映体：(R)- 和 (S)-NNAL，两者都是在人体中通过葡萄糖醛酸化作用广泛解毒。我们新颖的初步数据表明了强大且尿 (R)-NNAL-葡萄糖醛酸苷 (Gluc)/(S)-NNAL- 比率之间存在统计显着负相关两项独立的前瞻性队列研究中的葡萄糖和肺癌风险。此外，吸烟者纯合子主要 NNAL 葡萄糖醛酸化酶 UGT2B17 的缺失多态性具有显着的 3 倍与两个队列中至少具有一种功能性 UGT2B17 等位基因的患者相比，这些患者患肺癌的风险更高。这些数据强烈支持我们的假设，即 (R)-NNAL 在烟草诱发的肺癌发生中发挥关键作用，并且这表明我们已经确定了肺癌风险的新的重要表型和遗传标记。目标该提案的目的是评估 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的途径和肺癌风险。我们的目标是前瞻性地评估是否尿中特定 NNAL 异构体或葡萄糖苷酸的水平或比例与以下方面的肺癌风险相关：(1) 来自上海和新加坡三项队列研究的中国吸烟者，以及 (2) 白人和黑人吸烟者来自南方社区队列研究，并随后筛选和验证遗传变异与 NNAL 对映体和葡萄糖醛酸苷形成的变异性相关。这些研究应该提供对于理解肺部重要的变异性和建立表型和基因型至关重要癌症风险，并将有助于识别肺癌高风险吸烟者，以促进发展针对 NNK 代谢途径的化学预防策略。