Menthol cigarette smoking-related blood metabolites and lung cancer risk

总结

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.