Menthol cigarette smoking-related blood metabolites and lung cancer risk

摘要 非裔美国人(AA)患肺癌(LC)的负担不成比例地高--AA男性的 罹患LC和死于LC的可能性比任何其他种族和民族都要高。目前，几乎没有 了解导致LC差异的潜在因素。抽薄荷醇香烟是最有特色的 定义AA吸烟者的特征，导致人们猜测吸烟薄荷醇可能在一定程度上导致了， 对于AA中LC的额外负担。然而，迄今为止的流行病学研究并不能给出一个完整的解释。 通过问卷调查了解吸烟薄荷醇在LC病因中的作用和/或危害， 潜在的反向因果关系，以及AAs、薄荷醇吸烟者和被检查代谢物的数量不足。 此外，以往的研究并没有全面探讨薄荷醇香烟的潜在机制。 吸烟与肺癌的发生，突显了创新研究的必要性，以调查隐藏的线索 这可以解释美国汽车协会中与薄荷醇香烟吸烟相关的不成比例的负担和差异。至 填补流行病学证据方面的知识空白，解决薄荷醇香烟在LC中的实际危害 病因学方面，我们提出了第一项基于人群的前瞻性研究，纳入了多阶段代谢组学。 确定薄荷醇吸烟相关代谢物及其与LC风险之间关系的方法 全面、经济实惠的方式。利用诊断前的血液样本、丰富的流行病学数据，以及 最近在NCI资助的南方社区队列研究(SCCS)中生成的代谢组学数据 前瞻性队列，我们的目标是：1)使用 新陈代谢公司的全球代谢组学平台(8个超级途径中的~1,500个代谢物)在959种癌症中- 自由吸烟者(617名吸烟者和342名吸烟者)，并进一步评估薄荷醇的可能联系 与吸烟相关的血液代谢物与种族、性别、年龄、吸烟强度/持续时间等 已知/建议的LC危险因素(目标1)；和2)进行嵌套病例对照研究，以调查 每种薄荷醇吸烟相关代谢物与标准化代谢物风险评分的关系 有LC风险，使用诊断前的80对LC病例(腺癌)和 匹配的对照组，选自SCCS内无癌症的AA男性当前吸烟者(目标2)。 这项拟议研究的结果将增进我们对薄荷醇香烟实际危害的认识。 吸烟在LC病因学中的作用，为了解薄荷醇香烟的致病/分子途径提供了重要的见解 吸烟，并产生有价值的信息，以制定新的公共卫生战略，主要是预防LC 以种族/民族弱势群体为目标。此外，这项拟议的研究将带来一种机械性的 对吸烟薄荷醇的解释，这是导致LC负担过高的潜在因素 从而有助于阐明隐藏在LC种族/民族差异背后的线索，这填补了 关于吸烟者之间的吸烟悖论的LC差异研究中的知识差距。

SUMMARY African Americans (AAs) bear a disproportionately high burden of lung cancer (LC)―AA males have a much higher likelihood of developing LC and dying from LC than any other race and ethnic groups. Currently, little is known about the potential contributors to the LC disparities. Menthol cigarette smoking is the most distinctive feature that defines AA smokers, leading to speculation that menthol cigarette smoking may contribute, in part, to the extra burden of LC among AAs. However, epidemiologic studies to date could not bring a full explanation of the role and/or harms of menthol cigarette smoking in LC etiology owing to questionnaire-only investigations, potential reverse causality, and insufficient numbers of AAs, menthol smokers, and examined metabolites. Moreover, previous studies did not comprehensively explore the underlying mechanisms of menthol cigarette smoking and lung carcinogenesis, highlighting the need for innovative research to investigate the hidden clues that can explain disproportional burdens and disparities related to menthol cigarette smoking among AAs. To fill the knowledge gaps in epidemiologic evidence and address the actual hazards of menthol cigarettes in LC etiology, we propose the first population-based prospective study incorporating a multi-stage metabolomics approach to identify the menthol cigarette smoking-related metabolites and their associations with LC risk in a comprehensive and cost-efficient way. Leveraging pre-diagnostic blood samples, rich epidemiologic data, and recently generated metabolomics data in the Southern Community Cohort Study (SCCS), an NCI-funded prospective cohort, we aim to 1) identify menthol cigarette smoking-related blood metabolites using the Metabolon’s Global Metabolomics platform (~1,500 metabolites in eight super pathways) among 959 cancer- free current smokers (617 AAs and 342 EAs) and further evaluate the possible associations of menthol cigarette smoking-related blood metabolites with race, sex, age, smoking intensity/duration, and other known/suggested risk factors for LC (Aim 1); and 2) conduct a nested case-control study to investigate the associations of each menthol cigarette smoking-related metabolite and a standardized metabolite risk score with LC risk, using pre-diagnostic blood samples of 80 pairs of incident LC cases (adenocarcinoma) and matched controls who were selected from cancer-free AA male current smokers within the SCCS (Aim 2). Findings from this proposed study will advance our knowledge of the actual hazards of menthol cigarette smoking in LC etiology, provide important insight into the pathogenic/molecular pathways of menthol cigarette smoking, and generate valuable information to develop new public health strategies for LC prevention mainly targeted at racially/ethnically disadvantaged people. Furthermore, this proposed study will bring a mechanistic explanation of menthol cigarette smoking, a potential contributor to a disproportionately high burden of LC among AAs, and thus help elucidate hidden clues underlying the racial/ethnic disparities in LC, which fills the knowledge gaps in LC disparities research regarding the smoking paradox among AAs.