TY - JOUR
T1 - Epigenome-wide association study for lifetime estrogen exposure identifies an epigenetic signature associated with breast cancer risk
AU - Johansson, Annelie
AU - Palli, Domenico
AU - Masala, Giovanna
AU - Grioni, Sara
AU - Agnoli, Claudia
AU - Tumino, Rosario
AU - Giurdanella, Maria Concetta
AU - Fasanelli, Francesca
AU - Sacerdote, Carlotta
AU - Panico, Salvatore
AU - Mattiello, Amalia
AU - Polidoro, Silvia
AU - Jones, Michael E.
AU - Schoemaker, Minouk J.
AU - Orr, Nick
AU - Tomczyk, Katarzyna
AU - Johnson, Nichola
AU - Fletcher, Olivia
AU - Perduca, Vittorio
AU - Baglietto, Laura
AU - Dugué, Pierre Antoine
AU - Southey, Melissa C.
AU - Giles, Graham G.
AU - English, Dallas R.
AU - Milne, Roger L.
AU - Severi, Gianluca
AU - Ambatipudi, Srikant
AU - Cuenin, Cyrille
AU - Chajès, Veronique
AU - Romieu, Isabelle
AU - Herceg, Zdenko
AU - Swerdlow, Anthony J.
AU - Vineis, Paolo
AU - Flanagan, James M.
PY - 2019/4/30
Y1 - 2019/4/30
N2 - 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.
AB - 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.
KW - Biomarker
KW - Breast cancer
KW - Cancer risk
KW - DNA methylation
KW - Epigenetics
KW - Estrogen exposure
KW - EWAS
KW - Hormonal exposures
UR - http://www.scopus.com/inward/record.url?scp=85065140341&partnerID=8YFLogxK
U2 - 10.1186/s13148-019-0664-7
DO - 10.1186/s13148-019-0664-7
M3 - Article
C2 - 31039828
SN - 1868-7083
VL - 11
JO - Clinical Epigenetics
JF - Clinical Epigenetics
IS - 1
M1 - 66
ER -
