ABSTRACT
BACKGROUND: Several studies have suggested that global DNA methylation in circulating white blood cells (WBC) is associated with breast cancer risk. METHODS: To address conflicting results and concerns that the findings for WBC DNA methylation in some prior studies may reflect disease effects, we evaluated the relationship between global levels of WBC DNA methylation in white blood cells and breast cancer risk in a case-control study nested within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) cohort. A total of 428 invasive breast cancer cases and 419 controls, frequency matched on age at entry (55-59, 60-64, 65-69, ≥70 years), year of entry (on/before September 30, 1997, on/after October 1, 1997) and period of DNA extraction (previously extracted, newly extracted) were included. The ratio of 5-methyl-2' deoxycytidine [5-mdC] to 2'-deoxyguanine [dG], assuming [dG] = [5-mdC] + [2'-deoxycytidine [dC]] (%5-mdC), was determined by liquid chromatography-electrospray ionization-tandem mass spectrometry, an especially accurate method for assessing total genomic DNA methylation. RESULTS: Odds ratio (OR) estimates and 95% confidence intervals (CI) for breast cancer risk adjusted for age at entry, year of entry, and period of DNA extraction, were 1.0 (referent), 0.89 (95% CI, 0.6-1.3), 0.88 (95% CI, 0.6-1.3), and 0.84 (95% CI, 0.6-1.2) for women in the highest compared to lowest quartile levels of %5md-C (p for trend = .39). Effects did not meaningfully vary by time elapsed from WBC collection to diagnosis. DISCUSSION: These results do not support the hypothesis that global DNA hypomethylation in WBC DNA is associated with increased breast cancer risk prior to the appearance of clinical disease.
Subject(s)
Breast Neoplasms, Male/epidemiology , Breast Neoplasms/epidemiology , DNA Methylation/genetics , Leukocytes , Neoplastic Cells, Circulating , Biomarkers, Tumor/blood , Breast Neoplasms/etiology , Breast Neoplasms/pathology , Breast Neoplasms, Male/etiology , Breast Neoplasms, Male/pathology , Clinical Trials as Topic , Colorectal Neoplasms/blood , Colorectal Neoplasms/complications , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/genetics , Female , Humans , Lung Neoplasms/blood , Lung Neoplasms/complications , Lung Neoplasms/epidemiology , Lung Neoplasms/genetics , Male , Ovarian Neoplasms/blood , Ovarian Neoplasms/complications , Ovarian Neoplasms/epidemiology , Ovarian Neoplasms/genetics , Prostatic Neoplasms/blood , Prostatic Neoplasms/complications , Prostatic Neoplasms/epidemiology , Prostatic Neoplasms/genetics , Risk FactorsABSTRACT
It is not yet clear whether white blood cell DNA global methylation is associated with breast cancer risk. In this review we examine the relationships between multiple breast cancer risk factors and three markers of global DNA methylation: LINE-1, 5-mdC, and Alu. A literature search was conducted using Pubmed up to April 1, 2016, using combinations of relevant outcomes such as "WBC methylation," "blood methylation," "blood LINE-1 methylation," and a comprehensive list of known and suspected breast cancer risk factors. Overall, the vast majority of reports in the literature have focused on LINE-1. There was reasonably consistent evidence across the studies examined that males have higher levels of LINE-1 methylation in WBC DNA than females. None of the other demographic, lifestyle, dietary, or health condition risk factors were consistently associated with LINE-1 DNA methylation across studies. With the possible exception of sex, there was also little evidence that the wide range of breast cancer risk factors we examined were associated with either of the other two global DNA methylation markers: 5-mdC and Alu. One possible implication of the observed lack of association between global WBC DNA methylation and known breast cancer risk factors is that the association between global WBC DNA methylation and breast cancer, if it exists, is due to a disease effect.
