Gene-tobacco carcinogen interactions and lung cancer risk - a novel approach for precision cancer prevention

烟草特有的亚硝胺(4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone)被认为是 是导致吸烟者患肺癌的主要因素。NNK的代谢是复杂的，其 其致癌作用可能是通过其主要致癌代谢物4-(甲基亚硝基)-1- 3-吡啶-1-丁醇(NNAL)NNAL形成了两个对映体：(R)-和(S)-NNAL，它们都是 在人类中被葡萄糖醛酸化作用广泛解毒。我们新奇的初步数据显示了一个强有力的 尿(R)-NNAL-葡萄糖醛酸(Gluc)/(S)-NNAL-Gluc比值与尿(R)-NNAL-Gluc呈显著负相关 两项独立的前瞻性队列研究中的Gluc和肺癌风险。此外，吸烟者是纯合子 对于主要的NNAL-葡萄糖醛酸化酶UGT2B17的缺失多态，有显著的3倍 与两个队列中至少有一个功能性UGT2B17等位基因的人相比，患肺癌的风险更高。这些数据 有力地支持了我们的假设，即(R)-NNAL在烟草诱导的肺癌发生中发挥关键作用 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。目标是 这项建议的目的是评估NNAL对映体和葡萄糖醛酸苷在肺癌中的重要性 肿瘤的发生，并阐明NNAL形成和消除的新的表型和遗传标记 多个人群中的通路和肺癌风险。我们的目标是前瞻性地评估 尿中特定的NNAL异构体或葡萄糖醛酸苷的水平或比率与肺癌风险有关：(1) 来自上海和新加坡的三项队列研究中的中国吸烟者，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有关。这些研究应该提供 对理解变异性和建立在肺中重要的表型和基因型至关重要的洞察力 癌症风险，并将协助确定肺癌高危吸烟者的发展 针对NNK代谢途径的化学预防策略。

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.