Whole-Blood DNA Methylation Markers in Early Detection of Breast Cancer: A Systematic Literature Review

Abstract

Whole-blood DNA methylation markers have been suggested as potential biomarkers for early detection of breast cancer. We conducted a systematic review of the literature on whole-blood DNA methylation markers for breast cancer detection. PubMed and ISI Web of Knowledge were searched up to May 29, 2018. Overall, 33 studies evaluating 355 markers were included. The diagnostic value of most individual markers was relatively modest, with only six markers showing sensitivity >40% at specificity >75% [only 2 (HYAL2 and S100P) were independently validated]. Although relatively strong associations (OR 0.5 or OR 2) with breast cancer were reported for 14 markers, most of them were not independently validated. Two prospective studies performed epigenome-wide association analysis and identified 276 CpG sites related to breast cancer risk, but no overlap was observed between CpGs reported from these two studies. Five studies incorporated individual markers as panels, but only two of them used a test-validation approach. In conclusion, so far detected methylation markers are insufficient for breast cancer early detection, but markers or marker-combinations may be useful for breast cancer risk stratification. Utilizing high-throughput methods of methylation quantification, future studies should focus on further mining informative methylation markers and derivation of enhanced multimaker panels with thorough external validation ideally in prospective settings. Abbreviation: ref., reference. a Model adjusted for age, family history, age at menarche, parity, menopausal status, and body mass index. b No information for model covariates adjustment. c Model adjusted for age, family history, body mass index, and physical activity. d Model adjusted for age, race, family history of breast cancer, study site, menopausal status, parity, and age at menarche. e Crude odds ratio. f Model adjusted for menopausal status, age, and weight. g Statistical significance for OR.Guan et al.

Methylation silencing of TGF-β receptor type II is involved in malignant transformation of esophageal squamous cell carcinoma

“…Methylation of specific sites may therefore be of biological and further clinical value in the early detection of ESCC, which is urgent for more favorable outcomes in the treatment of patients. Hotspots for DNA methylation are also valuable as biomarkers in the so-called liquid biopsy for cancer diagnosis and therapy since they are not only detected in resected tissues, but also in various body fluids, including peripheral blood [33][34][35][36], saliva [37][38][39], and urine [40][41][42]. In fact, methylated APC [43] and CDKN2A [44] have already been detected in the plasma of a subset of ESCC patients.…”

Methylation profiling in promoter sequences of ATM and CDKN2A (p14ARF/p16INK4a) genes in blood and cfDNA from women with impalpable breast lesions

“…Hypomethylation and silencing of tumor suppressor gene expression by hypermethylation have been recognized as important markers for different cancers (14). Especially hypermethylation has been studied in DNA from WBC and revealed potential signatures to detect and predict breast cancer evolution (15,16). In this way, the CDKN2A (p14 ARF /p16 INK4a ) and ATM genes are potential targets for epigenetic study, as they are described as hypermethylated in breast carcinogenesis (17)(18)(19)(20)(21)(22)(23).…”

The Role of DNA Methylation in Ischemic Stroke: A Systematic Review

“…Since DNA methylation is influenced by many environmental exposures throughout the life course (9,10), it reflects the environment-gene interaction. It has been proved to be associated with some common diseases such as cancer (11)(12)(13)(14), psychiatric disorders (15), and dementia (16). Emerging evidence indicated the multi-faceted role of DNA methylation in various pathological mechanisms of cerebral ischemia (6).…”