American Association for Cancer Research
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Figure 1 from Cigarette Smoking and E-cigarette Use Induce Shared DNA Methylation Changes Linked to Carcinogenesis

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posted on 2024-06-04, 07:23 authored by Chiara Herzog, Allison Jones, Iona Evans, Janhavi R. Raut, Michal Zikan, David Cibula, Andrew Wong, Hermann Brenner, Rebecca C. Richmond, Martin Widschwendter

General overview of the study and identification of cell type–specific smoking-dependent epigenetic changes. A, Overview of the study. We aimed to identify cell- and tissue-specific epigenetic alterations and used a discovery set of buccal, cervical, and immune cells (all female). Findings were then validated in several independent sets to confirm the association with current and former smoking and explore association of cell-specific effects across smoking alternatives (e-cigarette use, moist tobacco use), lung cancer tissue and progression, and possibility to predict lung cancers in smokers using noninvasive samples. A detailed workflow of the analysis is shown in Supplementary Fig. S1. B, Scatterplots of methylation beta values in three CpGs located in the AHRR gene or intergenic region versus immune cell proportion (buccal and cervical samples) or lymphoid proportion (blood) indicate methylation differences may be derived from distinct cell types. C, Visualization of delta-beta values across four groups of CpGs identified in Supplementary Fig. S5A. A matrix of inferred delta-beta values across all tissues for all significant CpGs (i.e., significant in at least one tissue in the EWAS) was clustered using UMAP and the following clusters identified: epithelial hypomethylation (epithelial hypoM), immune hypomethylation (immune hypoM), distal epithelial hypermethylation (distal epithelial hyperM; effects in distal epithelium but not directly exposed epithelium), and proximal epithelial hypermethylation (proximal epithelial hypoM; effects in buccal/directly exposed samples only). (A, Created with


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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.

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