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Epigenome-wide association study for lifetime estrogen exposure identifies an epigenetic signature associated with breast cancer risk

  • Johansson, Annelie1
  • Palli, Domenico2
  • Masala, Giovanna2
  • Grioni, Sara3
  • Agnoli, Claudia3
  • Tumino, Rosario4
  • Giurdanella, Maria Concetta4
  • Fasanelli, Francesca5
  • Sacerdote, Carlotta5
  • Panico, Salvatore6
  • Mattiello, Amalia6
  • Polidoro, Silvia7
  • Jones, Michael E.8
  • Schoemaker, Minouk J.8
  • Orr, Nick9, 10
  • Tomczyk, Katarzyna10
  • Johnson, Nichola10
  • Fletcher, Olivia10
  • Perduca, Vittorio11
  • Baglietto, Laura12
  • And 14 more
  • 1 Imperial College London, Division of Cancer, Department of Surgery and Cancer, Faculty of Medicine, 4th Floor IRDB, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK , London (United Kingdom)
  • 2 Institute for Cancer Research Prevention and Clinical Network—ISPRO, Cancer Risk Factors and Lifestyle Epidemiology Unit, Florence, Italy , Florence (Italy)
  • 3 Fondazione IRCCS Istituto Nazionale dei Tumori, Epidemiology and Prevention Unit, Milan, Italy , Milan (Italy)
  • 4 Ragusa Cancer Registry, ASP, Ragusa, Italy , Ragusa (Italy)
  • 5 Città della Salute e della Scienza University-Hospital and Center for Cancer Prevention (CPO), Unit of Cancer Epidemiology, Turin, Italy , Turin (Italy)
  • 6 University of Naples Frederico II, Dipartimento di Medicina Clinica e Chirurgia, Naples, Italy , Naples (Italy)
  • 7 Italian Institute for Genomic Medicine, Turin, Italy , Turin (Italy)
  • 8 The Institute of Cancer Research, London, UK , London (United Kingdom)
  • 9 Queen’s University Belfast, Centre for Cancer Research and Cell Biology, Belfast, UK , Belfast (United Kingdom)
  • 10 The Institute of Cancer Research, The Breast Cancer Now Toby Robins Research Centre, London, UK , London (United Kingdom)
  • 11 Université Paris Descartes, MAP5 - UMR CNRS 8145, Paris, France , Paris (France)
  • 12 University of Pisa, Department of Clinical and Experimental Medicine, Pisa, Italy , Pisa (Italy)
  • 13 Cancer Council Victoria, Cancer Epidemiology and Intelligence Division, Melbourne, Australia , Melbourne (Australia)
  • 14 The University of Melbourne, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, Melbourne, Australia , Melbourne (Australia)
  • 15 Monash University, Precision Medicine, School of Clinical Sciences at Monash Health, Melbourne, Australia , Melbourne (Australia)
  • 16 The University of Melbourne, Genetic Epidemiology Laboratory, Department of Pathology, Parkville, Australia , Parkville (Australia)
  • 17 Université Paris-Saclay, UPS, UVSQ, Gustave Roussy, Centre de Recherche en Épidémiologie et Santé des Populations (CESP, Inserm U1018), Villejuif, France , Villejuif (France)
  • 18 International Agency for Research on Cancer (IARC), Lyon, France , Lyon (France)
  • 19 Sree Chitra Tirunal Institute for Medical Sciences and Technology, AMCHSS, Trivandrum, Kerala, 695011, India , Trivandrum (India)
  • 20 The Institute of Cancer Research, Division of Breast Cancer Research, London, UK , London (United Kingdom)
  • 21 Imperial College London, MRC-PHE Centre for Environment and Health, School of Public Health, London, UK , London (United Kingdom)
Published Article
Clinical Epigenetics
Publication Date
Apr 30, 2019
DOI: 10.1186/s13148-019-0664-7
Springer Nature


BackgroundIt is well established that estrogens and other hormonal factors influence breast cancer susceptibility. We hypothesized that a woman’s total lifetime estrogen exposure accumulates changes in DNA methylation, detectable in the blood, which could be used in risk assessment for breast cancer.MethodsAn estimated lifetime estrogen exposure (ELEE) model was defined using epidemiological data from EPIC-Italy (n = 31,864). An epigenome-wide association study (EWAS) of ELEE was performed using existing Illumina HumanMethylation450K Beadchip (HM450K) methylation data obtained from EPIC-Italy blood DNA samples (n = 216). A methylation index (MI) of ELEE based on 31 CpG sites was developed using HM450K data from EPIC-Italy and the Generations Study and evaluated for association with breast cancer risk in an independent dataset from the Generations Study (n = 440 incident breast cancer cases matched to 440 healthy controls) using targeted bisulfite sequencing. Lastly, a meta-analysis was conducted including three additional cohorts, consisting of 1187 case-control pairs.ResultsWe observed an estimated 5% increase in breast cancer risk per 1-year longer ELEE (OR = 1.05, 95% CI 1.04–1.07, P = 3 × 10−12) in EPIC-Italy. The EWAS identified 694 CpG sites associated with ELEE (FDR Q < 0.05). We report a DNA methylation index (MI) associated with breast cancer risk that is validated in the Generations Study targeted bisulfite sequencing data (ORQ4_vs_Q1 = 1.77, 95% CI 1.07–2.93, P = 0.027) and in the meta-analysis (ORQ4_vs_Q1 = 1.43, 95% CI 1.05–2.00, P = 0.024); however, the correlation between the MI and ELEE was not validated across study cohorts.ConclusionWe have identified a blood DNA methylation signature associated with breast cancer risk in this study. Further investigation is required to confirm the interaction between estrogen exposure and DNA methylation in the blood.

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