Global DNA methylation levels in white blood cell DNA from sisters discordant for breast cancer from the New York site of the Breast Cancer Family Registry

Abstract

Lower global DNA methylation is associated with genomic instability and it is one of the epigenetic mechanisms relevant to carcinogenesis. Emerging evidence for several cancers suggests that lower overall levels of global DNA methylation in blood are associated with different cancer types, although less is known about breast cancer. We examined global DNA methylation levels using a sibling design in 273 sisters affected with breast cancer and 335 unaffected sisters from the New York site of the Breast Cancer Family Registry. We measured global DNA methylation in total white blood cell (WBC) and granulocyte DNA by two different methods, the [ ( 3) H]-methyl acceptance assay and the luminometric methylation assay (LUMA). Global methylation levels were only modestly correlated between sisters discordant for breast cancer (Spearman correlation coefficients ranged from -0.08 to 0.24 depending on assay and DNA source). Using conditional logistic regression models, women in the quartile with the lowest DNA methylation levels (as measured by the [ ( 3) H]-methyl acceptance assay) had a 1.8-fold (95% CI = 1.0-3.3) higher relative association with breast cancer than women in the quartile with the highest DNA methylation levels. When we examined the association on a continuous scale, we also observed a positive association (odds ratio, OR = 1.3, 95% CI = 1.0-1.7, for a one unit change in the natural logarithm of the DPM/μg of DNA). We observed no association between measures by the LUMA assay and breast cancer risk. If replicated in prospective studies, this study suggests that global DNA methylation levels measured in WBC may be a potential biomarker of breast cancer risk even within families at higher risk of cancer.

Artificial light-at-night – a novel lifestyle risk factor for metabolic disorder and cancer morbidity

“…The genome of breast cancer cells is typically characterized by global hypo-methylation, and this assumption is supported by results of a meta-analysis study, in which breast cancer risk has been found to be significantly higher for women with the lowest GDM compared with the counterpart group with the highest GDM levels [169]. Global hypomethylation in white blood cells has also been reported to be related with increased risk of breast cancer [170,171]. Global DNA hypo-methylation can promote breast cancer development via several signaling pathways, including triggering genomic instability, activation of oncogenes, and inducing metastasis formations [172,173].…”

Differences in DNA methylation by extent of breast cancer family history in unaffected women

“…DNA methylation is one type of epigenetic change that has been associated with cancer, and recent studies have shown that global changes in DNA methylation in peripheral tissue such as blood are correlated with increased risk of different cancers, including breast. [6][7][8][9][10] Our group also found that global DNA methylation levels, measured by the methyl acceptance assay, and levels in the repeat Sat2 were lower in women with breast cancer when compared with their unaffected sisters. 7,8 Therefore, it has been hypothesized that lower global DNA methylation in peripheral tissue may be an indicator of an individual's susceptibility to breast cancer.…”

“…[6][7][8]19 However, lower levels of LINE-1 have been associated with increased risk of gastric, head and neck, bladder, liver, and testicular cancer. 17,[20][21][22][23] Increased breast cancer risk has been found to be related to lower DNA methylation of the repetitive element Sat2.…”

“…discordant for breast cancer suggesting that these markers might represent shared genetic and/or environmental determinants. 7,8 In a study investigating colorectal cancer risk, DNA methylation levels of LINE-1 in tumor DNA were associated with a family history of colorectal cancer. 12 We have also reported differences in global DNA methylation biomarkers in blood of girls with a family history of breast cancer when compared with those without.…”

DNA methylation as a promising landscape: A simple blood test for breast cancer prediction

“…In this regard, some researchers have suggested that methylation analysis of repetitive elements such as LINE1, sat2 and Alu in WBC may be a surrogate for genomic hypomethylation. Based on this approach, some studies have shown that these repetitive elements in the leukocytes of healthy women with a family history of breast cancer are hypomethylated [16,46] as well as breast cancer patients compared to controls [8,21,47].…”