Menthol cigarette smoking-related blood metabolites and lung cancer risk

总结 非裔美国人（AA）承担着不成比例的肺癌（LC）负担-AA男性有很多 发展LC和死于LC的可能性高于任何其他种族和族裔群体。目前， 了解LC差异的潜在贡献者。男性吸烟是最有特色的 定义AA吸烟者的特征，导致人们猜测，薄荷香烟吸烟可能有助于，部分， 信用证的额外负担。然而，迄今为止的流行病学研究还不能给出一个完整的解释。 薄荷醇香烟吸烟在LC病因学中的作用和/或危害， 潜在的反向因果关系，AA、薄荷醇吸烟者和检查的代谢物数量不足。 此外，以往的研究并没有全面探讨薄荷卷烟的潜在机制 吸烟和肺癌的发生，强调需要创新的研究，调查隐藏的线索 这可以解释与AAs中的薄荷醇香烟吸烟相关的不成比例的负担和差异。到 填补流行病学证据的知识空白，并解决薄荷醇香烟在LC中的实际危害 病因学，我们提出了第一个基于人群的前瞻性研究，包括多阶段代谢组学 方法来确定薄荷醇香烟吸烟相关的代谢物及其与LC风险的关联， 全面和具有成本效益的方式。利用诊断前血液样本、丰富的流行病学数据， 最近在南方社区队列研究（SCCS）中生成的代谢组学数据， 前瞻性队列，我们的目标是1）确定薄荷醇香烟吸烟相关的血液代谢物使用 Metabolon的全球代谢组学平台（在8个超级途径中约1，500种代谢物）在959种癌症中， 目前的自由吸烟者（617名AA和342名EA），并进一步评估薄荷醇的可能关联 与吸烟相关的血液代谢物与种族、性别、年龄、吸烟强度/持续时间和其他 已知/建议的LC风险因素（目标1）; 2）进行巢式病例对照研究， 每种薄荷醇香烟吸烟相关代谢物与标准化代谢物风险评分的相关性 使用80对LC病例（腺癌）的诊断前血液样本， 匹配的对照组，其选自SCCS内的无癌症AA男性当前吸烟者（目标2）。 这项研究的结果将促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，提供了对薄荷醇香烟致病/分子途径的重要见解 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 针对种族/族裔弱势群体。此外，这项研究将带来一种机制， 薄荷香烟吸烟的解释，一个潜在的贡献者不成比例的高负担LC ，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 知识差距在LC差距研究关于吸烟的矛盾之间的AA。

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.