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Blood DNA methylation and breast cancer risk: a meta-analysis of four prospective cohort studies

  • Bodelon, Clara1
  • Ambatipudi, Srikant2, 3
  • Dugué, Pierre-Antoine4, 5
  • Johansson, Annelie6
  • Sampson, Joshua N.1
  • Hicks, Belynda1, 7
  • Karlins, Eric1, 7
  • Hutchinson, Amy1, 7
  • Cuenin, Cyrille2
  • Chajès, Veronique2
  • Southey, Melissa C.8
  • Romieu, Isabelle2
  • Giles, Graham G.4, 5
  • English, Dallas4, 5
  • Polidoro, Silvia9, 10
  • Assumma, Manuela9, 10
  • Baglietto, Laura11
  • Vineis, Paolo12
  • Severi, Gianluca13
  • Herceg, Zdenko2
  • And 3 more
  • 1 National Cancer Institute, Divison of Cancer Epidemiology and Genetics, Bethesda, USA , Bethesda (United States)
  • 2 International Agency for Research on Cancer (IARC), Lyon, France , Lyon (France)
  • 3 AMCHSS, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India , Trivandrum (India)
  • 4 Cancer Council Victoria, Cancer Epidemiology and Intelligence Division, Melbourne, Victoria, Australia , Melbourne (Australia)
  • 5 The University of Melbourne, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, Melbourne, Victoria, Australia , Melbourne (Australia)
  • 6 Imperial College London, Division of Cancer, London, UK , London (United Kingdom)
  • 7 Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Cancer Genomics Research Laboratory, Frederick, USA , Frederick (United States)
  • 8 The University of Melbourne, Genetic Epidemiology Laboratory, Department of Pathology, Parkville, Australia , Parkville (Australia)
  • 9 IIGM (Italian Institute for Genomic Medicine), Turin, Italy , Turin (Italy)
  • 10 University of Turin, Department of Medical Sciences, Turin, Italy , Turin (Italy)
  • 11 University of Pisa, Department of Clinical and Experimental Medicine, Pisa, Italy , Pisa (Italy)
  • 12 Imperial College, MRC-PHE Center for Environment and Health, School of Public Health, London, UK , London (United Kingdom)
  • 13 UVSQ, Université Paris-Saclay, CESP (U1018 INSERM, Équipe Générations et Santé), Facultés de médecine Université Paris-Sud, Villejuif, France , Villejuif (France)
Published Article
Breast Cancer Research
Springer Science and Business Media LLC
Publication Date
May 17, 2019
DOI: 10.1186/s13058-019-1145-9
Springer Nature


BackgroundEnvironmental 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.MethodsWe 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.ResultsThe 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).ConclusionsOur 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.

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