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 Baglietto & 14 others Pierre 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 journalArticleResearchpeer-review

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
Number of pages12
JournalClinical Epigenetics
Volume11
Issue number1
DOIs
Publication statusPublished - 30 Apr 2019

Keywords

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

Cite this

Johansson, Annelie ; Palli, Domenico ; Masala, Giovanna ; Grioni, Sara ; Agnoli, Claudia ; Tumino, Rosario ; Giurdanella, Maria Concetta ; Fasanelli, Francesca ; Sacerdote, Carlotta ; Panico, Salvatore ; Mattiello, Amalia ; Polidoro, Silvia ; Jones, Michael E. ; Schoemaker, Minouk J. ; Orr, Nick ; Tomczyk, Katarzyna ; Johnson, Nichola ; Fletcher, Olivia ; Perduca, Vittorio ; Baglietto, Laura ; Dugué, Pierre Antoine ; Southey, Melissa C. ; Giles, Graham G. ; English, Dallas R. ; Milne, Roger L. ; Severi, Gianluca ; Ambatipudi, Srikant ; Cuenin, Cyrille ; Chajès, Veronique ; Romieu, Isabelle ; Herceg, Zdenko ; Swerdlow, Anthony J. ; Vineis, Paolo ; Flanagan, James M. / Epigenome-wide association study for lifetime estrogen exposure identifies an epigenetic signature associated with breast cancer risk. In: Clinical Epigenetics. 2019 ; Vol. 11, No. 1.
@article{aed69ecdd3934126ba2b67d8993a7c25,
title = "Epigenome-wide association study for lifetime estrogen exposure identifies an epigenetic signature associated with breast cancer risk",
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.",
keywords = "Biomarker, Breast cancer, Cancer risk, DNA methylation, Epigenetics, Estrogen exposure, EWAS, Hormonal exposures",
author = "Annelie Johansson and Domenico Palli and Giovanna Masala and Sara Grioni and Claudia Agnoli and Rosario Tumino and Giurdanella, {Maria Concetta} and Francesca Fasanelli and Carlotta Sacerdote and Salvatore Panico and Amalia Mattiello and Silvia Polidoro and Jones, {Michael E.} and Schoemaker, {Minouk J.} and Nick Orr and Katarzyna Tomczyk and Nichola Johnson and Olivia Fletcher and Vittorio Perduca and Laura Baglietto and Dugu{\'e}, {Pierre Antoine} and Southey, {Melissa C.} and Giles, {Graham G.} and English, {Dallas R.} and Milne, {Roger L.} and Gianluca Severi and Srikant Ambatipudi and Cyrille Cuenin and Veronique Chaj{\`e}s and Isabelle Romieu and Zdenko Herceg and Swerdlow, {Anthony J.} and Paolo Vineis and Flanagan, {James M.}",
year = "2019",
month = "4",
day = "30",
doi = "10.1186/s13148-019-0664-7",
language = "English",
volume = "11",
journal = "Clinical Epigenetics",
issn = "1868-7075",
publisher = "Springer-Verlag London Ltd.",
number = "1",

}

Johansson, A, Palli, D, Masala, G, Grioni, S, Agnoli, C, Tumino, R, Giurdanella, MC, Fasanelli, F, Sacerdote, C, Panico, S, Mattiello, A, Polidoro, S, Jones, ME, Schoemaker, MJ, Orr, N, Tomczyk, K, Johnson, N, Fletcher, O, Perduca, V, Baglietto, L, Dugué, PA, Southey, MC, Giles, GG, English, DR, Milne, RL, Severi, G, Ambatipudi, S, Cuenin, C, Chajès, V, Romieu, I, Herceg, Z, Swerdlow, AJ, Vineis, P & Flanagan, JM 2019, 'Epigenome-wide association study for lifetime estrogen exposure identifies an epigenetic signature associated with breast cancer risk', Clinical Epigenetics, vol. 11, no. 1, 66. https://doi.org/10.1186/s13148-019-0664-7

Epigenome-wide association study for lifetime estrogen exposure identifies an epigenetic signature associated with breast cancer risk. / Johansson, Annelie; Palli, Domenico; Masala, Giovanna; Grioni, Sara; Agnoli, Claudia; Tumino, Rosario; Giurdanella, Maria Concetta; Fasanelli, Francesca; Sacerdote, Carlotta; Panico, Salvatore; Mattiello, Amalia; Polidoro, Silvia; Jones, Michael E.; Schoemaker, Minouk J.; Orr, Nick; Tomczyk, Katarzyna; Johnson, Nichola; Fletcher, Olivia; Perduca, Vittorio; Baglietto, Laura; Dugué, Pierre Antoine; Southey, Melissa C.; Giles, Graham G.; English, Dallas R.; Milne, Roger L.; Severi, Gianluca; Ambatipudi, Srikant; Cuenin, Cyrille; Chajès, Veronique; Romieu, Isabelle; Herceg, Zdenko; Swerdlow, Anthony J.; Vineis, Paolo; Flanagan, James M.

In: Clinical Epigenetics, Vol. 11, No. 1, 66, 30.04.2019.

Research output: Contribution to journalArticleResearchpeer-review

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

VL - 11

JO - Clinical Epigenetics

JF - Clinical Epigenetics

SN - 1868-7075

IS - 1

M1 - 66

ER -