Cigarette Smoking and E-cigarette Use Induce Shared DNA Methylation Changes Linked to Carcinogenesis

Author:

Herzog Chiara12ORCID,Jones Allison3ORCID,Evans Iona3ORCID,Raut Janhavi R.45ORCID,Zikan Michal6ORCID,Cibula David7ORCID,Wong Andrew8ORCID,Brenner Hermann45ORCID,Richmond Rebecca C.910ORCID,Widschwendter Martin12311ORCID

Affiliation:

1. 1European Translational Oncology Prevention and Screening (EUTOPS) Institute, Universität Innsbruck, Innsbruck, Austria.

2. 2Research Institute for Biomedical Aging, Universität Innsbruck, Innsbruck, Austria.

3. 3Department of Women's Cancer, UCL EGA Institute for Women's Health, University College London, London, United Kingdom.

4. 4Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.

5. 5German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.

6. 6Department of Gynecology and Obstetrics, First Faculty of Medicine and Hospital Na Bulovce, Charles University in Prague, Prague, Czech Republic.

7. 7Gynecologic Oncology Center, Department of Obstetrics and Gynecology, First Faculty of Medicine, Charles University in Prague, General University Hospital in Prague, Prague, Czech Republic.

8. 8MRC Unit for Lifelong Health and Ageing, Institute of Cardiovascular Science, University College London, London, United Kingdom.

9. 9MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom.

10. 10Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.

11. 11Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.

Abstract

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. 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.

Funder

Horizon 2020 Framework Programme

The Eve Appeal

The Land Tirol

Cancer Research UK

Publisher

American Association for Cancer Research (AACR)

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