posted on 2024-06-04, 07:23authored byChiara Herzog, Allison Jones, Iona Evans, Janhavi R. Raut, Michal Zikan, David Cibula, Andrew Wong, Hermann Brenner, Rebecca C. Richmond, Martin Widschwendter
Evaluation of scores in independent validation sets. Independent dataset comprising 304 matched blood and buccal samples (n = 152 each) and 442 cervical samples was used to validate the findings. A–C, Mean beta values (uncorrected) in each of the four sets of CpGs in buccal (A), blood (B), and cervical (C) samples of never smokers, ex-smokers, and current smokers versus immune cell proportion (A and C) or lymphoid proportion (B). D–F, AUC of corrected values in each of the four sets of CpG comparing never smokers with current or former smokers in buccal (D), blood (E), and cervical (F) samples. Mean methylation scores in this figure only include sites present on the 450K array for comparability between datasets.
Funding
Horizon 2020 Framework Programme (H2020)
The Eve Appeal
The Land Tirol
Cancer Research UK (CRUK)
History
ARTICLE ABSTRACT
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.
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.