Srikant Ambatipudi1, Steve Horvath2, Flavie Perrier1, Cyrille Cuenin1, Hector Hernandez-Vargas1, Florence Le Calvez-Kelm1, Geoffroy Durand1, Graham Byrnes1, Pietro Ferrari1, Liacine Bouaoun1, Athena Sklias1, Véronique Chajes1, Kim Overvad3, Gianluca Severi4, Laura Baglietto5, Françoise Clavel-Chapelon6, Rudolf Kaaks7, Myrto Barrdahl7, Heiner Boeing8, Antonia Trichopoulou9, Pagona Lagiou10, Androniki Naska9, Giovanna Masala11, Claudia Agnoli12, Silvia Polidoro13, Rosario Tumino14, Salvatore Panico15, Martijn Dollé16, Petra H M Peeters17, N Charlotte Onland-Moret18, Torkjel M Sandanger19, Therese H Nøst19, Elisabete Weiderpass20, J Ramón Quirós21, Antonio Agudo22, Miguel Rodriguez-Barranco23, José María Huerta Castaño24, Aurelio Barricarte25, Ander Matheu Fernández26, Ruth C Travis27, Paolo Vineis28, David C Muller28, Elio Riboli28, Marc Gunter1, Isabelle Romieu1, Zdenko Herceg29. 1. International Agency for Research on Cancer (IARC), Lyon, France. 2. Human Genetics and Biostatistics, University of California Los Angeles, Los Angeles, CA 90095-7088, USA. 3. Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark. 4. Inserm, Centre de Recherche en Epidémiologie et Santé des Populations (CESP, U1018), Université Paris-Saclay, Université Paris-Sud, UVSQ, Institut Gustave Roussy, Villejuif, France; Human Genetics Foundation (HuGeF), Torino, Italy; Cancer Epidemiology Centre, Cancer Council Victoria and Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourn, Australia. 5. Inserm, Centre de Recherche en Epidémiologie et Santé des Populations (CESP, U1018), Université Paris-Saclay, Université Paris-Sud, UVSQ, Institut Gustave Roussy, Villejuif, France; Cancer Epidemiology Centre, Cancer Council Victoria and Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourn, Australia. 6. Inserm, Centre de Recherche en Epidémiologie et Santé des Populations (CESP, U1018), Université Paris-Saclay, Université Paris-Sud, UVSQ, Institut Gustave Roussy, Villejuif, France. 7. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 8. Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany. 9. Hellenic Health Foundation, Athens, Greece; WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece. 10. Hellenic Health Foundation, Athens, Greece; WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece; Department of Epidemiology, Harvard School of Public Health, Boston, USA. 11. Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute - ISPO, Florence, Italy. 12. Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy. 13. Human Genetics Foundation (HuGeF), Torino, Italy. 14. Cancer Registry and Histopathology Unit, "Civic M.P. Arezzo" Hospital, ASP Ragusa, Italy. 15. Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy. 16. Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. 17. Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands; MRC-PHE Centre for Environment and Health, Dept of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, UK. 18. Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands. 19. Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway. 20. Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway; Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Genetic Epidemiology Group, Folkhälsan Research Center, Helsinki, Finland. 21. Public Health Directorate, Asturias, Spain. 22. Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain. 23. Escuela Andaluza de Salud Pública, Instituto de Investigación Biosanitaria ibsn Granada, Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain; CIBER de Epidemiología y Salud Pública (CIBERESP), Spain. 24. Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain; CIBER de Epidemiología y Salud Pública (CIBERESP), Spain. 25. Navarra Public Health Institute, Pamplona, Spain; Navarra Institute for Health Research (IdiSNA) Pamplona, Spain; CIBER de Epidemiología y Salud Pública (CIBERESP), Spain. 26. Cellular Oncology Group, Biodonostia Health Research Institute, Paseo Dr. Beguiristain s/n, San Sebastian, Spain; IKERBASQUE, Basque Foundation, Spain. 27. Cancer Epidemiology Unit, Nuffield Department of Population Health University of Oxford, Oxford UK. 28. School of Public Health, Imperial College London, London, UK. 29. International Agency for Research on Cancer (IARC), Lyon, France. Electronic address: herceg@iarc.fr.
Abstract
AIM OF THE STUDY: A vast majority of human malignancies are associated with ageing, and age is a strong predictor of cancer risk. Recently, DNA methylation-based marker of ageing, known as 'epigenetic clock', has been linked with cancer risk factors. This study aimed to evaluate whether the epigenetic clock is associated with breast cancer risk susceptibility and to identify potential epigenetics-based biomarkers for risk stratification. METHODS: Here, we profiled DNA methylation changes in a nested case-control study embedded in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (n = 960) using the Illumina HumanMethylation 450K BeadChip arrays and used the Horvath age estimation method to calculate epigenetic age for these samples. Intrinsic epigenetic age acceleration (IEAA) was estimated as the residuals by regressing epigenetic age on chronological age. RESULTS: We observed an association between IEAA and breast cancer risk (OR, 1.04; 95% CI, 1.007-1.076, P = 0.016). One unit increase in IEAA was associated with a 4% increased odds of developing breast cancer (OR, 1.04; 95% CI, 1.007-1.076). Stratified analysis based on menopausal status revealed that IEAA was associated with development of postmenopausal breast cancers (OR, 1.07; 95% CI, 1.020-1.11, P = 0.003). In addition, methylome-wide analyses revealed that a higher mean DNA methylation at cytosine-phosphate-guanine (CpG) islands was associated with increased risk of breast cancer development (OR per 1 SD = 1.20; 95 %CI: 1.03-1.40, P = 0.02) whereas mean methylation levels at non-island CpGs were indistinguishable between cancer cases and controls. CONCLUSION: Epigenetic age acceleration and CpG island methylation have a weak, but statistically significant, association with breast cancer susceptibility.
AIM OF THE STUDY: A vast majority of human malignancies are associated with ageing, and age is a strong predictor of cancer risk. Recently, DNA methylation-based marker of ageing, known as 'epigenetic clock', has been linked with cancer risk factors. This study aimed to evaluate whether the epigenetic clock is associated with breast cancer risk susceptibility and to identify potential epigenetics-based biomarkers for risk stratification. METHODS: Here, we profiled DNA methylation changes in a nested case-control study embedded in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (n = 960) using the Illumina HumanMethylation 450K BeadChip arrays and used the Horvath age estimation method to calculate epigenetic age for these samples. Intrinsic epigenetic age acceleration (IEAA) was estimated as the residuals by regressing epigenetic age on chronological age. RESULTS: We observed an association between IEAA and breast cancer risk (OR, 1.04; 95% CI, 1.007-1.076, P = 0.016). One unit increase in IEAA was associated with a 4% increased odds of developing breast cancer (OR, 1.04; 95% CI, 1.007-1.076). Stratified analysis based on menopausal status revealed that IEAA was associated with development of postmenopausal breast cancers (OR, 1.07; 95% CI, 1.020-1.11, P = 0.003). In addition, methylome-wide analyses revealed that a higher mean DNA methylation at cytosine-phosphate-guanine (CpG) islands was associated with increased risk of breast cancer development (OR per 1 SD = 1.20; 95 %CI: 1.03-1.40, P = 0.02) whereas mean methylation levels at non-island CpGs were indistinguishable between cancer cases and controls. CONCLUSION: Epigenetic age acceleration and CpG island methylation have a weak, but statistically significant, association with breast cancer susceptibility.
Authors: Kristin Wallace; Maria V Grau; A Joan Levine; Lanlan Shen; Randala Hamdan; Xinli Chen; Jiang Gui; Robert W Haile; Elizabeth L Barry; Dennis Ahnen; Gail McKeown-Eyssen; John A Baron; Jean Pierre J Issa Journal: Cancer Prev Res (Phila) Date: 2010-12
Authors: E Riboli; K J Hunt; N Slimani; P Ferrari; T Norat; M Fahey; U R Charrondière; B Hémon; C Casagrande; J Vignat; K Overvad; A Tjønneland; F Clavel-Chapelon; A Thiébaut; J Wahrendorf; H Boeing; D Trichopoulos; A Trichopoulou; P Vineis; D Palli; H B Bueno-De-Mesquita; P H M Peeters; E Lund; D Engeset; C A González; A Barricarte; G Berglund; G Hallmans; N E Day; T J Key; R Kaaks; R Saracci Journal: Public Health Nutr Date: 2002-12 Impact factor: 4.022
Authors: Iñigo Martincorena; Amit Roshan; Moritz Gerstung; Peter Ellis; Peter Van Loo; Stuart McLaren; David C Wedge; Anthony Fullam; Ludmil B Alexandrov; Jose M Tubio; Lucy Stebbings; Andrew Menzies; Sara Widaa; Michael R Stratton; Philip H Jones; Peter J Campbell Journal: Science Date: 2015-05-22 Impact factor: 47.728
Authors: Riccardo E Marioni; Sonia Shah; Allan F McRae; Stuart J Ritchie; Graciela Muniz-Terrera; Sarah E Harris; Jude Gibson; Paul Redmond; Simon R Cox; Alison Pattie; Janie Corley; Adele Taylor; Lee Murphy; John M Starr; Steve Horvath; Peter M Visscher; Naomi R Wray; Ian J Deary Journal: Int J Epidemiol Date: 2015-01-22 Impact factor: 7.196
Authors: Steve Horvath; Paolo Garagnani; Maria Giulia Bacalini; Chiara Pirazzini; Stefano Salvioli; Davide Gentilini; Anna Maria Di Blasio; Cristina Giuliani; Spencer Tung; Harry V Vinters; Claudio Franceschi Journal: Aging Cell Date: 2015-02-09 Impact factor: 9.304
Authors: Anthony S Zannas; Janine Arloth; Tania Carrillo-Roa; Stella Iurato; Simone Röh; Kerry J Ressler; Charles B Nemeroff; Alicia K Smith; Bekh Bradley; Christine Heim; Andreas Menke; Jennifer F Lange; Tanja Brückl; Marcus Ising; Naomi R Wray; Angelika Erhardt; Elisabeth B Binder; Divya Mehta Journal: Genome Biol Date: 2015-12-17 Impact factor: 13.583
Authors: Morgan E Levine; H Dean Hosgood; Brian Chen; Devin Absher; Themistocles Assimes; Steve Horvath Journal: Aging (Albany NY) Date: 2015-09 Impact factor: 5.682
Authors: Steve Horvath; Michael Gurven; Morgan E Levine; Benjamin C Trumble; Hillard Kaplan; Hooman Allayee; Beate R Ritz; Brian Chen; Ake T Lu; Tammy M Rickabaugh; Beth D Jamieson; Dianjianyi Sun; Shengxu Li; Wei Chen; Lluis Quintana-Murci; Maud Fagny; Michael S Kobor; Philip S Tsao; Alexander P Reiner; Kerstin L Edlefsen; Devin Absher; Themistocles L Assimes Journal: Genome Biol Date: 2016-08-11 Impact factor: 13.583
Authors: Sarah W Curtis; Dawayland O Cobb; Varun Kilaru; Metrecia L Terrell; M Elizabeth Marder; Dana Boyd Barr; Carmen J Marsit; Michele Marcus; Karen N Conneely; Alicia K Smith Journal: Epigenetics Date: 2019-06-14 Impact factor: 4.528
Authors: Sheri J Hartman; Sandahl H Nelson; Emily Myers; Loki Natarajan; Dorothy D Sears; Barton W Palmer; Lauren S Weiner; Barbara A Parker; Ruth E Patterson Journal: Cancer Date: 2017-09-19 Impact factor: 6.860
Authors: Alexandra M Binder; Camila Corvalan; Verónica Mericq; Ana Pereira; José Luis Santos; Steve Horvath; John Shepherd; Karin B Michels Journal: Epigenetics Date: 2018-02-15 Impact factor: 4.528
Authors: Martin Widschwendter; Allison Jones; Iona Evans; Daniel Reisel; Joakim Dillner; Karin Sundström; Ewout W Steyerberg; Yvonne Vergouwe; Odette Wegwarth; Felix G Rebitschek; Uwe Siebert; Gaby Sroczynski; Inez D de Beaufort; Ineke Bolt; David Cibula; Michal Zikan; Line Bjørge; Nicoletta Colombo; Nadia Harbeck; Frank Dudbridge; Anne-Marie Tasse; Bartha M Knoppers; Yann Joly; Andrew E Teschendorff; Nora Pashayan Journal: Nat Rev Clin Oncol Date: 2018-02-27 Impact factor: 66.675