Susceptibility to hormone-mediated cancer is reflected by different tick rates of the epithelial and general epigenetic clock
Abstract 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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-02-01
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| Series: | Genome Biology |
| Online Access: | https://doi.org/10.1186/s13059-022-02603-3 |
| _version_ | 1818984904276312064 |
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| author | James E. Barrett Chiara Herzog Yoo-Na Kim Thomas E. Bartlett Allison Jones Iona Evans David Cibula Michal Zikan Line Bjørge Nadia Harbeck Nicoletta Colombo Sacha J. Howell Angelique Flöter Rådestad Kristina Gemzell-Danielsson Martin Widschwendter |
| author_facet | James E. Barrett Chiara Herzog Yoo-Na Kim Thomas E. Bartlett Allison Jones Iona Evans David Cibula Michal Zikan Line Bjørge Nadia Harbeck Nicoletta Colombo Sacha J. Howell Angelique Flöter Rådestad Kristina Gemzell-Danielsson Martin Widschwendter |
| author_sort | James E. Barrett |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-20T18:26:25Z |
| format | Article |
| id | doaj.art-12a38f2cd1054cb4b89b25ca9f11ff1b |
| institution | Directory Open Access Journal |
| issn | 1474-760X |
| language | English |
| last_indexed | 2024-12-20T18:26:25Z |
| publishDate | 2022-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Biology |
| spelling | doaj.art-12a38f2cd1054cb4b89b25ca9f11ff1b2022-12-21T19:30:09ZengBMCGenome Biology1474-760X2022-02-0123111610.1186/s13059-022-02603-3Susceptibility to hormone-mediated cancer is reflected by different tick rates of the epithelial and general epigenetic clockJames E. Barrett0Chiara Herzog1Yoo-Na Kim2Thomas E. Bartlett3Allison Jones4Iona Evans5David Cibula6Michal Zikan7Line Bjørge8Nadia Harbeck9Nicoletta Colombo10Sacha J. Howell11Angelique Flöter Rådestad12Kristina Gemzell-Danielsson13Martin Widschwendter14European Translational Oncology Prevention and Screening (EUTOPS) InstituteEuropean Translational Oncology Prevention and Screening (EUTOPS) InstituteEuropean Translational Oncology Prevention and Screening (EUTOPS) InstituteDepartment of Statistical Science, University College LondonDepartment of Women’s Cancer, UCL EGA Institute for Women’s Health, University College LondonDepartment of Women’s Cancer, UCL EGA Institute for Women’s Health, University College LondonGynaecologic Oncology Center, Department of Obstetrics and Gynecology, First Faculty of Medicine, Charles University in Prague, General University Hospital in PragueDepartment of Gynecology and Obstetrics, Charles University in Prague, First Faculty of Medicine and University Hospital BulovkaDepartment of Obstetrics and Gynaecology, Haukeland University HospitalBreast Center, Department of Obstetrics and Gynecology, University of Munich (LMU)Istituto Europeo di Oncologia IRCCSBreast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of ManchesterDepartment of Women’s and Children’s Health, Karolinska Institutet and Karolinska University HospitalDepartment of Women’s and Children’s Health, Karolinska Institutet and Karolinska University HospitalEuropean Translational Oncology Prevention and Screening (EUTOPS) InstituteAbstract 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.https://doi.org/10.1186/s13059-022-02603-3 |
| spellingShingle | James E. Barrett Chiara Herzog Yoo-Na Kim Thomas E. Bartlett Allison Jones Iona Evans David Cibula Michal Zikan Line Bjørge Nadia Harbeck Nicoletta Colombo Sacha J. Howell Angelique Flöter Rådestad Kristina Gemzell-Danielsson Martin Widschwendter Susceptibility to hormone-mediated cancer is reflected by different tick rates of the epithelial and general epigenetic clock Genome Biology |
| title | Susceptibility to hormone-mediated cancer is reflected by different tick rates of the epithelial and general epigenetic clock |
| title_full | Susceptibility to hormone-mediated cancer is reflected by different tick rates of the epithelial and general epigenetic clock |
| title_fullStr | Susceptibility to hormone-mediated cancer is reflected by different tick rates of the epithelial and general epigenetic clock |
| title_full_unstemmed | Susceptibility to hormone-mediated cancer is reflected by different tick rates of the epithelial and general epigenetic clock |
| title_short | Susceptibility to hormone-mediated cancer is reflected by different tick rates of the epithelial and general epigenetic clock |
| title_sort | susceptibility to hormone mediated cancer is reflected by different tick rates of the epithelial and general epigenetic clock |
| url | https://doi.org/10.1186/s13059-022-02603-3 |
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