Blood DNA methylation and breast cancer risk

A meta-analysis of four prospective cohort studies

Clara Bodelon, Srikant Ambatipudi, Pierre Antoine Dugué, Annelie Johansson, Joshua N. Sampson, Belynda Hicks, Eric Karlins, Amy Hutchinson, Cyrille Cuenin, Veronique Chajès, Melissa C. Southey, Isabelle Romieu, Graham G. Giles, Dallas English, Silvia Polidoro, Manuela Assumma, Laura Baglietto, Paolo Vineis, Gianluca Severi, Zdenko Herceg & 3 others James M. Flanagan, Roger L. Milne, Montserrat Garcia-Closas

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

Abstract

Background: Environmental and genetic factors play an important role in the etiology of breast cancer. Several small blood-based DNA methylation studies have reported risk associations with methylation at individual CpGs and average methylation levels; however, these findings require validation in larger prospective cohort studies. To investigate the role of blood DNA methylation on breast cancer risk, we conducted a meta-analysis of four prospective cohort studies, including a total of 1663 incident cases and 1885 controls, the largest study of blood DNA methylation and breast cancer risk to date. Methods: We assessed associations with methylation at 365,145 CpGs present in the HumanMethylation450 (HM450K) Beadchip, after excluding CpGs that did not pass quality controls in all studies. Each of the four cohorts estimated odds ratios (ORs) and 95% confidence intervals (CI) for the association between each individual CpG and breast cancer risk. In addition, each study assessed the association between average methylation measures and breast cancer risk, adjusted and unadjusted for cell-type composition. Study-specific ORs were combined using fixed-effect meta-analysis with inverse variance weights. Stratified analyses were conducted by age at diagnosis (< 50, ≥ 50), estrogen receptor (ER) status (+/-), and time since blood collection (< 5, 5-10, > 10 years). The false discovery rate (q value) was used to account for multiple testing. Results: The average age at blood draw ranged from 52.2 to 62.2 years across the four cohorts. Median follow-up time ranged from 6.6 to 8.4 years. The methylation measured at individual CpGs was not associated with breast cancer risk (q value > 0.59). In addition, higher average methylation level was not associated with risk of breast cancer (OR = 0.94, 95% CI = 0.85, 1.05; P = 0.26; P for study heterogeneity = 0.86). We found no evidence of modification of this association by age at diagnosis (P = 0.17), ER status (P = 0.88), time since blood collection (P = 0.98), or CpG location (P = 0.98). Conclusions: Our data indicate that DNA methylation measured in the blood prior to breast cancer diagnosis in predominantly postmenopausal women is unlikely to be associated with substantial breast cancer risk on the HM450K array. Larger studies or with greater methylation coverage are needed to determine if associations exist between blood DNA methylation and breast cancer risk.

Original languageEnglish
Article number62
Number of pages9
JournalBreast Cancer Research
Volume21
Issue number1
DOIs
Publication statusPublished - 17 May 2019
Externally publishedYes

Keywords

  • Blood DNA methylation
  • Breast cancer risk
  • Meta-analysis
  • Prospective study

Cite this

Bodelon, C., Ambatipudi, S., Dugué, P. A., Johansson, A., Sampson, J. N., Hicks, B., ... Garcia-Closas, M. (2019). Blood DNA methylation and breast cancer risk: A meta-analysis of four prospective cohort studies. Breast Cancer Research, 21(1), [62]. https://doi.org/10.1186/s13058-019-1145-9
Bodelon, Clara ; Ambatipudi, Srikant ; Dugué, Pierre Antoine ; Johansson, Annelie ; Sampson, Joshua N. ; Hicks, Belynda ; Karlins, Eric ; Hutchinson, Amy ; Cuenin, Cyrille ; Chajès, Veronique ; Southey, Melissa C. ; Romieu, Isabelle ; Giles, Graham G. ; English, Dallas ; Polidoro, Silvia ; Assumma, Manuela ; Baglietto, Laura ; Vineis, Paolo ; Severi, Gianluca ; Herceg, Zdenko ; Flanagan, James M. ; Milne, Roger L. ; Garcia-Closas, Montserrat. / Blood DNA methylation and breast cancer risk : A meta-analysis of four prospective cohort studies. In: Breast Cancer Research. 2019 ; Vol. 21, No. 1.
@article{eefecc6f6e04418c8cc96060d784c1d4,
title = "Blood DNA methylation and breast cancer risk: A meta-analysis of four prospective cohort studies",
abstract = "Background: Environmental and genetic factors play an important role in the etiology of breast cancer. Several small blood-based DNA methylation studies have reported risk associations with methylation at individual CpGs and average methylation levels; however, these findings require validation in larger prospective cohort studies. To investigate the role of blood DNA methylation on breast cancer risk, we conducted a meta-analysis of four prospective cohort studies, including a total of 1663 incident cases and 1885 controls, the largest study of blood DNA methylation and breast cancer risk to date. Methods: We assessed associations with methylation at 365,145 CpGs present in the HumanMethylation450 (HM450K) Beadchip, after excluding CpGs that did not pass quality controls in all studies. Each of the four cohorts estimated odds ratios (ORs) and 95{\%} confidence intervals (CI) for the association between each individual CpG and breast cancer risk. In addition, each study assessed the association between average methylation measures and breast cancer risk, adjusted and unadjusted for cell-type composition. Study-specific ORs were combined using fixed-effect meta-analysis with inverse variance weights. Stratified analyses were conducted by age at diagnosis (< 50, ≥ 50), estrogen receptor (ER) status (+/-), and time since blood collection (< 5, 5-10, > 10 years). The false discovery rate (q value) was used to account for multiple testing. Results: The average age at blood draw ranged from 52.2 to 62.2 years across the four cohorts. Median follow-up time ranged from 6.6 to 8.4 years. The methylation measured at individual CpGs was not associated with breast cancer risk (q value > 0.59). In addition, higher average methylation level was not associated with risk of breast cancer (OR = 0.94, 95{\%} CI = 0.85, 1.05; P = 0.26; P for study heterogeneity = 0.86). We found no evidence of modification of this association by age at diagnosis (P = 0.17), ER status (P = 0.88), time since blood collection (P = 0.98), or CpG location (P = 0.98). Conclusions: Our data indicate that DNA methylation measured in the blood prior to breast cancer diagnosis in predominantly postmenopausal women is unlikely to be associated with substantial breast cancer risk on the HM450K array. Larger studies or with greater methylation coverage are needed to determine if associations exist between blood DNA methylation and breast cancer risk.",
keywords = "Blood DNA methylation, Breast cancer risk, Meta-analysis, Prospective study",
author = "Clara Bodelon and Srikant Ambatipudi and Dugu{\'e}, {Pierre Antoine} and Annelie Johansson and Sampson, {Joshua N.} and Belynda Hicks and Eric Karlins and Amy Hutchinson and Cyrille Cuenin and Veronique Chaj{\`e}s and Southey, {Melissa C.} and Isabelle Romieu and Giles, {Graham G.} and Dallas English and Silvia Polidoro and Manuela Assumma and Laura Baglietto and Paolo Vineis and Gianluca Severi and Zdenko Herceg and Flanagan, {James M.} and Milne, {Roger L.} and Montserrat Garcia-Closas",
year = "2019",
month = "5",
day = "17",
doi = "10.1186/s13058-019-1145-9",
language = "English",
volume = "21",
journal = "Breast Cancer Research",
issn = "1465-5411",
publisher = "Springer-Verlag London Ltd.",
number = "1",

}

Bodelon, C, Ambatipudi, S, Dugué, PA, Johansson, A, Sampson, JN, Hicks, B, Karlins, E, Hutchinson, A, Cuenin, C, Chajès, V, Southey, MC, Romieu, I, Giles, GG, English, D, Polidoro, S, Assumma, M, Baglietto, L, Vineis, P, Severi, G, Herceg, Z, Flanagan, JM, Milne, RL & Garcia-Closas, M 2019, 'Blood DNA methylation and breast cancer risk: A meta-analysis of four prospective cohort studies', Breast Cancer Research, vol. 21, no. 1, 62. https://doi.org/10.1186/s13058-019-1145-9

Blood DNA methylation and breast cancer risk : A meta-analysis of four prospective cohort studies. / Bodelon, Clara; Ambatipudi, Srikant; Dugué, Pierre Antoine; Johansson, Annelie; Sampson, Joshua N.; Hicks, Belynda; Karlins, Eric; Hutchinson, Amy; Cuenin, Cyrille; Chajès, Veronique; Southey, Melissa C.; Romieu, Isabelle; Giles, Graham G.; English, Dallas; Polidoro, Silvia; Assumma, Manuela; Baglietto, Laura; Vineis, Paolo; Severi, Gianluca; Herceg, Zdenko; Flanagan, James M.; Milne, Roger L.; Garcia-Closas, Montserrat.

In: Breast Cancer Research, Vol. 21, No. 1, 62, 17.05.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Blood DNA methylation and breast cancer risk

T2 - A meta-analysis of four prospective cohort studies

AU - Bodelon, Clara

AU - Ambatipudi, Srikant

AU - Dugué, Pierre Antoine

AU - Johansson, Annelie

AU - Sampson, Joshua N.

AU - Hicks, Belynda

AU - Karlins, Eric

AU - Hutchinson, Amy

AU - Cuenin, Cyrille

AU - Chajès, Veronique

AU - Southey, Melissa C.

AU - Romieu, Isabelle

AU - Giles, Graham G.

AU - English, Dallas

AU - Polidoro, Silvia

AU - Assumma, Manuela

AU - Baglietto, Laura

AU - Vineis, Paolo

AU - Severi, Gianluca

AU - Herceg, Zdenko

AU - Flanagan, James M.

AU - Milne, Roger L.

AU - Garcia-Closas, Montserrat

PY - 2019/5/17

Y1 - 2019/5/17

N2 - Background: Environmental and genetic factors play an important role in the etiology of breast cancer. Several small blood-based DNA methylation studies have reported risk associations with methylation at individual CpGs and average methylation levels; however, these findings require validation in larger prospective cohort studies. To investigate the role of blood DNA methylation on breast cancer risk, we conducted a meta-analysis of four prospective cohort studies, including a total of 1663 incident cases and 1885 controls, the largest study of blood DNA methylation and breast cancer risk to date. Methods: We assessed associations with methylation at 365,145 CpGs present in the HumanMethylation450 (HM450K) Beadchip, after excluding CpGs that did not pass quality controls in all studies. Each of the four cohorts estimated odds ratios (ORs) and 95% confidence intervals (CI) for the association between each individual CpG and breast cancer risk. In addition, each study assessed the association between average methylation measures and breast cancer risk, adjusted and unadjusted for cell-type composition. Study-specific ORs were combined using fixed-effect meta-analysis with inverse variance weights. Stratified analyses were conducted by age at diagnosis (< 50, ≥ 50), estrogen receptor (ER) status (+/-), and time since blood collection (< 5, 5-10, > 10 years). The false discovery rate (q value) was used to account for multiple testing. Results: The average age at blood draw ranged from 52.2 to 62.2 years across the four cohorts. Median follow-up time ranged from 6.6 to 8.4 years. The methylation measured at individual CpGs was not associated with breast cancer risk (q value > 0.59). In addition, higher average methylation level was not associated with risk of breast cancer (OR = 0.94, 95% CI = 0.85, 1.05; P = 0.26; P for study heterogeneity = 0.86). We found no evidence of modification of this association by age at diagnosis (P = 0.17), ER status (P = 0.88), time since blood collection (P = 0.98), or CpG location (P = 0.98). Conclusions: Our data indicate that DNA methylation measured in the blood prior to breast cancer diagnosis in predominantly postmenopausal women is unlikely to be associated with substantial breast cancer risk on the HM450K array. Larger studies or with greater methylation coverage are needed to determine if associations exist between blood DNA methylation and breast cancer risk.

AB - Background: Environmental and genetic factors play an important role in the etiology of breast cancer. Several small blood-based DNA methylation studies have reported risk associations with methylation at individual CpGs and average methylation levels; however, these findings require validation in larger prospective cohort studies. To investigate the role of blood DNA methylation on breast cancer risk, we conducted a meta-analysis of four prospective cohort studies, including a total of 1663 incident cases and 1885 controls, the largest study of blood DNA methylation and breast cancer risk to date. Methods: We assessed associations with methylation at 365,145 CpGs present in the HumanMethylation450 (HM450K) Beadchip, after excluding CpGs that did not pass quality controls in all studies. Each of the four cohorts estimated odds ratios (ORs) and 95% confidence intervals (CI) for the association between each individual CpG and breast cancer risk. In addition, each study assessed the association between average methylation measures and breast cancer risk, adjusted and unadjusted for cell-type composition. Study-specific ORs were combined using fixed-effect meta-analysis with inverse variance weights. Stratified analyses were conducted by age at diagnosis (< 50, ≥ 50), estrogen receptor (ER) status (+/-), and time since blood collection (< 5, 5-10, > 10 years). The false discovery rate (q value) was used to account for multiple testing. Results: The average age at blood draw ranged from 52.2 to 62.2 years across the four cohorts. Median follow-up time ranged from 6.6 to 8.4 years. The methylation measured at individual CpGs was not associated with breast cancer risk (q value > 0.59). In addition, higher average methylation level was not associated with risk of breast cancer (OR = 0.94, 95% CI = 0.85, 1.05; P = 0.26; P for study heterogeneity = 0.86). We found no evidence of modification of this association by age at diagnosis (P = 0.17), ER status (P = 0.88), time since blood collection (P = 0.98), or CpG location (P = 0.98). Conclusions: Our data indicate that DNA methylation measured in the blood prior to breast cancer diagnosis in predominantly postmenopausal women is unlikely to be associated with substantial breast cancer risk on the HM450K array. Larger studies or with greater methylation coverage are needed to determine if associations exist between blood DNA methylation and breast cancer risk.

KW - Blood DNA methylation

KW - Breast cancer risk

KW - Meta-analysis

KW - Prospective study

UR - http://www.scopus.com/inward/record.url?scp=85066032941&partnerID=8YFLogxK

U2 - 10.1186/s13058-019-1145-9

DO - 10.1186/s13058-019-1145-9

M3 - Article

VL - 21

JO - Breast Cancer Research

JF - Breast Cancer Research

SN - 1465-5411

IS - 1

M1 - 62

ER -