Prediagnostic White Blood Cell DNA Methylation and Risk of Breast Cancer in the Prostate Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) Cohort

Cancer Epidemiol Biomarkers Prev. 2021 Aug;30(8):1575-1581. doi: 10.1158/1055-9965.EPI-20-1717. Epub 2021 Jun 9.


Background: White blood cell (WBC) DNA may contain methylation patterns that are associated with subsequent breast cancer risk. Using a high-throughput array and samples collected, on average, 1.3 years prior to diagnosis, a case-cohort analysis nested in the prospective Sister Study identified 250 individual CpG sites that were differentially methylated between breast cancer cases and noncases. We examined five of the top 40 CpG sites in a case-control study nested in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) Cohort.

Methods: We investigated the associations between prediagnostic WBC DNA methylation in 297 breast cancer cases and 297 frequency-matched controls. Two WBC DNA specimens from each participant were used: a proximate sample collected 1 to 2.9 years and a distant sample collected 4.2-7.3 years prior to diagnosis in cases or the comparable timepoints in controls. WBC DNA methylation level was measured using targeted bisulfite amplification sequencing. We used logistic regression to obtain ORs and 95% confidence intervals (CI).

Results: A one-unit increase in percent methylation in ERCC1 in proximate WBC DNA was associated with increased breast cancer risk (adjusted OR = 1.29; 95% CI, 1.06-1.57). However, a one-unit increase in percent methylation in ERCC1 in distant WBC DNA was inversely associated with breast cancer risk (adjusted OR = 0.83; 95% CI, 0.69-0.98). None of the other ORs met the threshold for statistical significance.

Conclusions: There was no convincing pattern between percent methylation in the five CpG sites and breast cancer risk.

Impact: The link between prediagnostic WBC DNA methylation marks and breast cancer, if any, is poorly understood.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Intramural

MeSH terms

  • Aged
  • Breast Neoplasms / genetics*
  • Case-Control Studies
  • Cell Cycle Proteins / genetics
  • CpG Islands
  • DNA Methylation*
  • DNA-Binding Proteins / genetics
  • Endonucleases / genetics
  • Female
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Leukocytes*
  • Membrane Proteins / genetics
  • Membrane Transport Proteins / genetics
  • Middle Aged
  • Mitochondrial Proteins / genetics
  • Prospective Studies


  • CAVIN3 protein, human
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • MCUR1 protein, human
  • Membrane Proteins
  • Membrane Transport Proteins
  • Mitochondrial Proteins
  • OPTN protein, human
  • ERCC1 protein, human
  • Endonucleases