UNLABELLED: Tobacco use is a major modifiable risk factor for adverse health outcomes, including cancer, and elicits profound epigenetic changes thought to be associated with long-term cancer risk. While electronic cigarettes (e-cigarettes) have been advocated as harm reduction alternatives to tobacco products, recent studies have revealed potential detrimental effects, highlighting the urgent need for further research into the molecular and health impacts of e-cigarettes. Here, we applied computational deconvolution methods to dissect the cell- and tissue-specific epigenetic effects of tobacco or e-cigarette use on DNA methylation (DNAme) in over 3,500 buccal/saliva, cervical, or blood samples, spanning epithelial and immune cells at directly and indirectly exposed sites. The 535 identified smoking-related DNAme loci [cytosine-phosphate-guanine sites (CpG)] clustered into four functional groups, including detoxification or growth signaling, based on cell type and anatomic site. Loci hypermethylated in buccal epithelial cells of smokers associated with NOTCH1/RUNX3/growth factor receptor signaling also exhibited elevated methylation in cancer tissue and progressing lung carcinoma in situ lesions, and hypermethylation of these sites predicted lung cancer development in buccal samples collected from smokers up to 22 years prior to diagnosis, suggesting a potential role in driving carcinogenesis. Alarmingly, these CpGs were also hypermethylated in e-cigarette users with a limited smoking history. This study sheds light on the cell type-specific changes to the epigenetic landscape induced by smoking-related products. SIGNIFICANCE: The use of both cigarettes and e-cigarettes elicits cell- and exposure-specific epigenetic effects that are predictive of carcinogenesis, suggesting caution when broadly recommending e-cigarettes as aids for smoking cessation.

Department of Gynecology and Obstetrics 1st Faculty of Medicine and Hospital Na Bulovce Charles University Prague Prague Czech Republic

Department of Women's and Children's Health Karolinska Institutet Stockholm Sweden

Department of Women's Cancer UCL EGA Institute for Women's Health University College London London United Kingdom

Division of Clinical Epidemiology and Aging Research German Cancer Research Center Heidelberg Germany

European Translational Oncology Prevention and Screening Institute Universität Innsbruck Innsbruck Austria

German Cancer Consortium Heidelberg Germany

Gynecologic Oncology Center Department of Obstetrics and Gynecology 1st Faculty of Medicine Charles University Prague General University Hospital Prague Prague Czech Republic

MRC Integrative Epidemiology Unit at the University of Bristol Bristol United Kingdom

MRC Unit for Lifelong Health and Ageing Institute of Cardiovascular Science University College London London United Kingdom

Population Health Sciences Bristol Medical School University of Bristol Bristol United Kingdom

Research Institute for Biomedical Aging Universität Innsbruck Innsbruck Austria

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Asia Pac J Public Health. 2024 Sep;36(6-7):646-647. doi: 10.1177/10105395241273180. PubMed

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