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

Annelie Johansson, Domenico Palli, Giovanna Masala, Sara Grioni, Claudia Agnoli, Rosario Tumino, Maria Concetta Giurdanella, Francesca Fasanelli, Carlotta Sacerdote, Salvatore Panico, Amalia Mattiello, Silvia Polidoro, Michael E. Jones, Minouk J. Schoemaker, Nick Orr, Katarzyna Tomczyk, Nichola Johnson, Olivia Fletcher, Vittorio Perduca, Laura BagliettoPierre Antoine Dugué, Melissa C. Southey, Graham G. Giles, Dallas R. English, Roger L. Milne, Gianluca Severi, Srikant Ambatipudi, Cyrille Cuenin, Veronique Chajès, Isabelle Romieu, Zdenko Herceg, Anthony J. Swerdlow, Paolo Vineis, James M. Flanagan

Research output: Contribution to journalArticle

Abstract

Background: It 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. Methods: An 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. Results: We 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 (OR Q4-vs-Q1 = 1.77, 95% CI 1.07-2.93, P = 0.027) and in the meta-analysis (OR Q4-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. Conclusion: We 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.

Original languageEnglish
Article number66
JournalClinical Epigenetics
Volume11
Issue number1
DOIs
Publication statusPublished - Apr 30 2019

Keywords

  • Biomarker
  • Breast cancer
  • Cancer risk
  • DNA methylation
  • Epigenetics
  • Estrogen exposure
  • EWAS
  • Hormonal exposures

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Developmental Biology
  • Genetics(clinical)

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    Johansson, A., Palli, D., Masala, G., Grioni, S., Agnoli, C., Tumino, R., Giurdanella, M. C., Fasanelli, F., Sacerdote, C., Panico, S., Mattiello, A., Polidoro, S., Jones, M. E., Schoemaker, M. J., Orr, N., Tomczyk, K., Johnson, N., Fletcher, O., Perduca, V., ... Flanagan, J. M. (2019). Epigenome-wide association study for lifetime estrogen exposure identifies an epigenetic signature associated with breast cancer risk. Clinical Epigenetics, 11(1), [66]. https://doi.org/10.1186/s13148-019-0664-7