Epigenome-wide DNA methylation and risk of breast cancer: a systematic review

Abstract

Background DNA methylation is a potential biomarker for early detection of breast cancer. However, robust evidence of a prospective relationship between DNA methylation patterns and breast cancer risk is still lacking. The objective of this study is to provide a systematic analysis of the findings of epigenome-wide DNA methylation studies on breast cancer risk, in light of their methodological strengths and weaknesses. Methods We searched major databases (MEDLINE, EMBASE, Web of Science, CENTRAL) from inception up to 30th June 2019, for observational or intervention studies investigating the association between epigenome-wide DNA methylation (using the HM450k or EPIC BeadChip), measured in any type of human sample, and breast cancer risk. A pre-established protocol was drawn up following the Cochrane Reviews rigorous methodology. Study selection, data abstraction, and risk of bias assessment were performed by at least two investigators. A qualitative synthesis and systematic comparison of the strengths and weaknesses of studies was performed. Results Overall, 20 studies using the HM450k BeadChip were included, 17 of which had measured blood-derived DNA methylation. There was a consistent trend toward an association of global blood-derived DNA hypomethylation and higher epigenetic age with higher risk of breast cancer. The strength of associations was modest for global hypomethylation and relatively weak for most of epigenetic age algorithms. Differences in length of follow-up periods may have influenced the ability to detect associations, as studies reporting follow-up periods shorter than 10 years were more likely to observe an association with global DNA methylation. Probe-wise differential methylation analyses identified between one and 806 differentially methylated CpGs positions in 10 studies. None of the identified differentially methylated sites overlapped between studies. Three studies used breast tissue DNA and suffered major methodological issues that precludes any conclusion. Overall risk of bias was critical mainly because of incomplete control of confounding. Important issues relative to data preprocessing could have limited the consistency of results. Conclusions Global DNA methylation may be a short-term predictor of breast cancer risk. Further studies with rigorous methodology are needed to determine spatial distribution of DNA hypomethylation and identify differentially methylated sites associated with risk of breast cancer. Prospero registration number CRD42020147244

Paradoxical effects of obesity on pre‑ vs. post‑menopausal breast cancer: The epigenetic mechanisms (Review)

“…Genes [e.g., the DNA repair gene, O-6-methylguanine-DNA methyltransferase (MGMT)] within these regions were largely silenced in BC cells and the loss of DNA methylation in these regions was accompanied by the formation of repressive chromatin, indicating a widespread DNA hypomethylation for gene regulation through chromatin alteration (62). A recent systematic analysis found an association between global blood-derived DNA hypomethylation with a higher risk of developing BC, and the strength of the association tends to be weak for long period follow-up, indicating that global DNA methylation may be a short-term predictor of the risk of developing BC (64).…”

“…As described above, substantial evidence has supported the associations between obesity and DNA methylation (80)(81)(82)91,92); however, the cause and effect remains to be defined. It is also well known that alterations in DNA methylation patterns are common epigenetic aberrations in BC (64,93). Dysregulated DNA methylation is directly associated with BC pathogenesis by controlling significant processes, including gene transcription, post-translation, the remodeling of chromatin, the imprinting of a genome, etc.…”

Impact of Stilbenes as Epigenetic Modulators of Breast Cancer Risk and Associated Biomarkers

“…However, there are some limitations to considering global methylation as a stable and strong biomarker for breast cancer risk determination. As pointed out by Ennour-Idrissi et al, the methylation signatures are subject to reversibility and variability based on tissue type [ 47 ]. To increase the precision of global methylation as a biomarker for breast cancer risk detection, collective methylation change in the global CpG landscape is being considered [ 48 ].…”

Association of mammographic density with blood DNA methylation

“…A developing avenue of research involves examining DNA methylation in surrogate tissues, such as blood. A number of studies have shown that epigenome-wide DNA methylation in white blood cells, especially at non-promoter regions, is associated with decreased breast cancer risk (reviewed in [ 23 ]).…”