Blood-based DNA methylation as biomarker for breast cancer: a systematic review

Abstract

Multiple studies have investigated global DNA methylation profiles and gene-specific DNA methylation in blood-based DNA to develop powerful screening markers for cancer. This systematic review summarizes the current evidence on methylation studies that investigated methylation level of blood-derived DNA of breast cancer (BC) patients in comparison to healthy controls by conducting a systematic literature review in PubMed and Web of Science. Essential results, such as methylation levels of BC cases and healthy controls, p values, and odds ratios, were extracted from these studies by two investigators independently. Overall, 45 publications met the inclusion criteria for this review. DNA from whole blood, as well as cell-free DNA (cfDNA) from serum or plasma, was used in these studies. The most common method used for measuring global DNA methylation was the investigation of repetitive elements as surrogates and the application of array-based genome-wide methylation analysis. For measuring gene-specific methylation level, methylation-specific PCR and pyrosequencing were the most frequently used methods. Epigenome-wide blood DNA hypomethylation in BC patients were reported in several studies; however, the evidence is still not conclusive. The most frequently investigated gene in whole blood was BRCA1, which was found more frequently methylated in patients compared to controls. RASSF1A was the most widely investigated gene in cfDNA of serum or plasma, which was also found more frequently methylated in patients compared to controls. Several of the eligible studies reported the associations of global hypomethylation and increased BC risk. Studies investigated associations between gene-specific methylation and BC risk, while got heterogeneous results. But two studies reported that hypermethylation of ATM gene was associated with increased BC risk, which suggest the potential use of this gene for BC risk stratification. Overall, our review suggests the possibility of using blood-based DNA methylation marker as promising marker for BC risk stratification, as several studies found associations between certain methylation level in blood and BC risk. However, so far, the evidence is still quite limited. Optimal markers are yet to be developed and promising results needed to be validated in prospective study cohorts and tested in large screening populations.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0282-6) contains supplementary material, which is available to authorized users.

Molecular Biology In Young Women With Breast Cancer: From Tumor Gene Expression To Dna Mutations

“…Aberrant methylation patterns in tumor cells are associated with the development of BC 50,51 . Wong et al 52 demonstrated that the constitutional DNA methylation of the BRCA1 promoter was significantly associated with an increased risk of early-onset BC in women under the age of 40 years.…”

Relationships between Global DNA Methylation in Circulating White Blood Cells and Breast Cancer Risk Factors

“…Although the possibility that global DNA methylation reflects a novel breast cancer risk factor cannot be ruled out on the basis of these findings, a plausible implication of the observed lack of association between global WBC DNA methylation and most known or suspected 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 [16, 59]. …”

Dietary fat and obesity as modulators of breast cancer risk: Focus on DNA methylation

“…Global hypomethylation contributes to cancer development and progression through activation of oncogenes (Van Tongelen, Loriot, & De Smet, ) and chromosomal instability (Gaudet et al, ). Changes in global CpG methylation can be monitored by measuring the methylation of repetitive elements in DNA (e.g., LINE‐1 and Alu) or the per cent of methylated DNA by luminometric methylation assay (LUMA), using mean methylation intensities of Infinium HumanMethylation 450 k probes (β‐value), or quantifying the concentration of 5‐methyldeoxycytosine (5‐mdC; Tang, Cheng, Cao, Surowy, & Burwinkel, ). Using the β‐value approach, a study reported an inverse association between BC incidence and global CpG methylation (OR = 0.42; 95% CI [0.20, 0.90]) in peripheral blood of BC patients ( n = 420; Severi et al, ).…”