BACKGROUND: A variety of epigenetic clocks utilizing DNA methylation changes have been developed; these clocks are either tissue-independent or designed to predict chronological age based on blood or saliva samples. Whether discordant tick rates between tissue-specific and general epigenetic clocks play a role in health and disease has not yet been explored. RESULTS: Here we analyze 1941 cervical cytology samples, which contain a mixture of hormone-sensitive cervical epithelial cells and immune cells, and develop the WID general clock (Women's IDentification of risk), an epigenetic clock that is shared by epithelial and immune cells and optimized for cervical samples. We then develop the WID epithelial clock and WID immune clock, which define epithelial- and immune-specific clocks, respectively. We find that the WID-relative-epithelial-age (WID-REA), defined as the difference between the epithelial and general clocks, is significantly reduced in cervical samples from pre-menopausal women with breast cancer (OR 2.7, 95% CI 1.28-5.72). We find the same effect in normal breast tissue samples from pre-menopausal women at high risk of breast cancer and show that potential risk reducing anti-progesterone drugs can reverse this. In post-menopausal women, this directionality is reversed. Hormone replacement therapy consistently leads to a significantly lower WID-REA in cancer-free women, but not in post-menopausal women with breast or ovarian cancer. CONCLUSIONS: Our findings imply that there are multiple epigenetic clocks, many of which are tissue-specific, and that the differential tick rate between these clocks may be an informative surrogate measure of disease risk.

Breast Biology Group Manchester Breast Centre Division of Cancer Sciences Faculty of Biology Medicine and Health University of Manchester Manchester UK

Breast Center Department of Obstetrics and Gynecology University of Munich Munich Germany

Centre for Cancer Biomarkers CCBIO Department of Clinical Science University of Bergen Bergen Norway

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

Department of Obstetrics and Gynaecology Haukeland University Hospital Bergen Norway

Department of Statistical Science University College London WC1E 7HB London UK

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

Department of Women's Cancer UCL EGA Institute for Women's Health University College London Medical School Building Room 340 74 Huntley Street WC1E 6AU London UK

European Translational Oncology Prevention and Screening Institute Milser Str 10 6060 Hall in Tirol Austria

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

Istituto Europeo di Oncologia IRCCS Milan Italy

Research Institute for Biomedical Aging Research Universität Innsbruck 6020 Innsbruck Austria

University of Milano Bicocca Milan Italy

Genome Biol. 2022 Jun 29;23(1):142. doi: 10.1186/s13059-022-02704-z. PubMed

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

Author Correction: Susceptibility to hormone-mediated cancer is reflected by different tick rates of the epithelial and general epigenetic clock