• DNA methylation
• breast cancer
• clinicopathological features
• panel
• ensitivity/specificity

• Aged
• Female
• Humans
• Breast Neoplasms/genetics
• Breast Neoplasms/pathology
• DNA Methylation
• ErbB Receptors/genetics
• Promoter Regions, Genetic
• Southeast Asian People
• Epigenomics
• Vietnam

Breast cancer has become a fatal disease for women world-wide. Its incidence in China has been increasing yearly, and the identification of early-stage biomarkers is urgently required.

ANOVA was carried out in the case of a primary tumor, adjacent normal tissue, and tumor metastasis of breast cancer, and on pan-cancer samples using the genome-wide methylation data of 31 solid tumor Illumina Methylation 450K chips downloaded from The Cancer Genome Atlas (TCGA) website in September 2018. Methylation sites showing a significant difference (P ≤ 0.05) were screened and compared with the whole-genome methylation data of 31 other solid tumor species in the TCGA database using t-tests in order to screen the methylation sites of breast cancer-specific expression. The expression of the screened methylation sites was confirmed through pyrosequencing in 45 cases of breast cancer, lung cancer, gastric cancer, and colorectal cancer.

A total of 10 specific breast cancer methylation sites (cg13683194, cg07996594, cg21646032, cg07671949, cg21185686, cg03625109, cg16429070, cg23601468, cg24818566, and cg01240931) were analyzed; nine genes (C9orf125, RARB, ESR1, RUNX3, PCDHGB7, DBC1, PDGFRB, TIMP3, and APC) were involved. The overall effect was excellent; a total of 4 methylation sites (2 in the DBC1 gene [cg03625109 and cg24818566], 1 in the C9orf125 gene [cg13683194], and 1 in the PDGFRB gene [cg16429070]) could effectively distinguish breast cancer from 31 other cancer species. The pyrosequencing results revealed that 7 screened methylation sites could significantly distinguish between breast cancer, lung cancer, gastric cancer, and colorectal cancer samples; these sites could also specifically distinguish between luminal A, luminal B, HER2, and Basal-like types of breast cancer.

The 10 breast cancer methylation sites screened in the present study can effectively distinguish breast cancer from 31 other solid tumors, and they are expected to be used as biomarkers for early screening of breast cancer.

• Research on molecular markers for early diagnosis and prognosis of breast cancer based on tumor ctDNA detection technology

With the recent advancement of genetic screening for testing susceptibility to mammary oncogenesis in women, the relevance of the gene−environment interaction has become progressively apparent in the context of aberrant gene expressions. Fetal exposure to external stressors, hormones, and nutrients, along with the inherited genome, impact its traits, including cancer susceptibility. Currently, there is increasing interest in the role of epigenetic biomarkers such as genomic methylation signatures, plasma microRNAs, and alterations in cell-signaling pathways in the diagnosis and primary prevention of breast cancer, as well as its prognosis. Polyphenols like natural stilbenes have been shown to be effective in chemoprevention by exerting cytotoxic effects that can stall cell proliferation. Besides possessing antioxidant properties against the DNA-damaging effects of reactive oxygen species, stilbenes have also been observed to modulate cell-signaling pathways. With the increasing trend of early-life screening for hereditary breast cancer risks, the potency of different phytochemicals in harnessing the epigenetic biomarkers of breast cancer risk demand more investigation. This review will explore means of exploiting the abilities of stilbenes in altering the underlying factors that influence breast cancer risk, as well as the appearance of associated biomarkers.

• biomarkers
• breast cancer
• cell-signaling
• epigenetics
• methylation
• microRNAs
• polyphenols
• prevention
• stilbene

• Animals
• Biomarkers/metabolism
• Breast Neoplasms/drug therapy
• Breast Neoplasms/metabolism
• Epigenomics
• Female
• Humans
• MicroRNAs/metabolism
• Polyphenols/metabolism
• Stilbenes/pharmacology

• R01 CA178441 NCI NIH HHS
• R01 CA204346 NCI NIH HHS
• NCI R01CA178441 NIH HHS
• NCI R01CA204346 NIH HHS

• biomarkers
• cell-free DNA
• circulating tumor DNA
• liquid biopsy
• precision oncology

• DNA methylation
• cell-free DNA
• circulating tumor DNA
• circulating tumor cells
• methylation-specific PCR
• minimal residual disease

• Biomarkers, Tumor/genetics
• Circulating Tumor DNA/genetics
• DNA Methylation/genetics
• Drug Resistance, Neoplasm/genetics
• Epigenesis, Genetic
• Humans
• Neoplasms/drug therapy
• Neoplasms/genetics

• breast cancer
• cell-free DNA
• cfDNA
• circulating DNA
• diagnostic accuracy
• diagnostic marker

• endometrial neoplasms
• uterine cancer

• Circulating Tumor DNA/blood
• Endometrial Neoplasms/blood
• Endometrial Neoplasms/mortality
• Female
• Humans
• Mutation
• Neoplasm Recurrence, Local
• Retrospective Studies
• Survival Analysis

• autoimmune diseases
• cancer diagnosis
• circulating cell free nucleic acids
• circulating nucleic acids in plasma/serum
• epigenetic biomarkers
• precision medicine
• prenatal and genetic diagnostics

Circulating tumor DNA (ctDNA) is an attractive source for liquid biopsy to understand molecular phenotypes of a tumor non-invasively, which is also expected to be both a diagnostic and prognostic marker. PIK3CA and KRAS are among the most frequently mutated genes in epithelial ovarian cancer (EOC). In addition, their hotspot mutations have already been identified and are ready for a highly sensitive analysis. Our aim is to clarify the significance of PIK3CA and KRAS mutations in the plasma of EOC patients as tumor-informed ctDNA.

We screened 306 patients with ovarian tumors for somatic PIK3CA or KRAS mutations. A total of 85 EOC patients had somatic PIK3CA and/or KRAS mutations, and the corresponding mutations were subsequently analyzed using a droplet digital polymerase chain reaction in their plasma.

The detection rates for ctDNA were 27% in EOC patients. Advanced stage and positive peritoneal cytology were associated with higher frequency of ctDNA detection. Preoperative ctDNA detection was found to be an indicator of outcomes, and multivariate analysis revealed that ctDNA remained an independent risk factor for recurrence (p=0.010). Moreover, we assessed the mutation frequency in matched plasma before surgery and at recurrence from 17 patients, and found six patients had higher mutation rates in cell-free DNA at recurrence compared to that at primary diagnosis.

The presence of ctDNA at diagnosis was an indicator for recurrence, which suggests potential tumor spread even when tumors were localized at the time of diagnosis.

• Biomarker
• KRAS
• Ovarian neoplasms
• PIK3CA
• ctDNA

• Liquid biopsy
• cell-free nucleic acids (cfNAs)
• circulating tumor cells (CTCs)
• exosomes

• breast cancer
• discriminative CpG dinucleotides
• early detection
• hypermethylation
• liquid biopsy

• Breast cancer biomarkers
• Colorimetric detection
• Enzyme-linked immunosorbent assay
• Self-assembly
• Smartphones
• pH indicators

• Biomarkers, Tumor/blood
• Biosensing Techniques/methods
• Breast Neoplasms/blood
• Breast Neoplasms/diagnosis
• Colorimetry/methods
• Enzyme-Linked Immunosorbent Assay/methods
• Female
• Humans
• Hydrogen-Ion Concentration
• Limit of Detection
• Nanoparticles/chemistry
• Nanoparticles/ultrastructure
• Point-of-Care Systems
• Receptor, ErbB-2/blood
• Receptors, Estrogen/blood
• Receptors, Progesterone/blood
• Smartphone

• breast cancer
• chromatin
• epigenomics
• mammary
• transcriptional regulation

• Adult
• Animals
• Breast Neoplasms/genetics
• Cell Line, Tumor
• Evolution, Molecular
• Female
• Gene Expression Profiling/methods
• Gene Expression Regulation, Neoplastic
• Gene Regulatory Networks
• Genetic Heterogeneity
• Humans
• Mammary Glands, Human/chemistry
• Mice
• Mutation
• Neoplasm Transplantation

• BC Cancer Foundation Strategic Priorities Fund
• CIHR Banting and Best Research Studentship
• 702851 Canadian Cancer Society Research Institute
• 22416 Cancer Research Society

Background: Numerous studies reported that RAS-association domain family 1 isoform A (RASSF1A) methylation might act as diagnostic biomarker for breast cancer (BC), this meta-analysis aimed to evaluate the value of RASSF1A methylation for diagnosing BC.

Methods: Such databases as PubMed, Cochrane Library and Web of Science databases were searched for literatures until May 2019. A meta-analysis was performed utilizing STATA and Revman softwares. Furthermore, subgroup analysis was adopted to determine likely sources of heterogeneity.

Results: Totally 19 literatures with 1849 patients and 1542 controls were included in the present study. Sensitivity, specificity, diagnostic odds ratio (DOR) and the area under the summary receiver operating characteristic curve (AUC) of RASSF1A methylation for diagnosing BC were 0.49, 0.95, 19.0 and 0.83, respectively. The sensitivity (0.54 vs 0.43), DOR (30.0 vs 10.0) and AUC (0.84 vs 0.81) of RASSF1A methylation in Caucasian were higher than other ethnicities. The sensitivity (0.64 vs 0.57), DOR (21.0 vs 14.0) and AUC (0.89 vs 0.86) of methylation-specific PCR (MSP) were superior to other methods (q-MSP, OS-MSP and MethyLight). The sensitivity, DOR and AUC of serum RASSF1A methylation vs RASSF1A methylation in other samples (tissue or plasma) were 0.55 vs 0.40, 22.0 vs 14.0 and 0.86 vs 0.74, respectively.

Conclusions: RASSF1A methylation might be a potential diagnostic biomarker for BC. Considering its low sensitivity and high specificity, it should combine with others to upgrade the sensitivity. Besides, under such conditions, MSP detection, serum RASSF1A methylation and Caucasian are shown to be more effective and suitable for diagnosing BC.

• DNA methylation
• RASSF1A
• breast cancer
• diagnosis
• meta-analysis

• Bisulfite conversion
• Circulating cell-free DNA
• DNA methylation
• Plasma
• Quantitative methylation-specific PCR

This study explored the value of measuring programmed death 1 (PD-1) in peripheral blood, combined with breast ultrasound using the Breast Imaging Reporting and Data System (BI-RADS) classification, for differentiation between benign and malignant breast tumors.

We enrolled 113 patients with breast cancer and 66 patients with benign breast tumors who were admitted to Hangzhou First People’s Hospital from September 2014 to August 2017. The mRNA level of PD-1 was detected by quantitative real-time polymerase chain reaction.

The mRNA levels of PD-1 were significantly higher in the peripheral blood of patients with breast cancer than those in patients with benign breast tumors. The diagnostic sensitivity of PD-1 mRNA expression was 0.805, the specificity was 0.788, and the area under the curve (AUC) was 0.848 (P < 0.001); the sensitivity of breast ultrasound-based BI-RADS classification was 0.752, the specificity was 0.909, and the AUC was 0.906 (P < 0.001); and the combined sensitivity, specificity, and AUC of the two assays were 0.920, 0.879, and 0.938, respectively (P < 0.001). Progesterone receptor-positive breast cancer patients exhibited high levels of PD-1 expression (P < 0.001).

This study suggests that the measurement of PD-1 combined with breast ultrasound-based BI-RADS classification represents a significant improvement for breast cancer diagnosis compared with diagnoses based on either method alone.

• PD-1
• breast cancer
• breast ultrasound
• diagnosis

• Breast cancer 1 (BRCA1)
• RAS-association domain family member 1 (RASSF1A)

• Asian People/genetics
• BRCA1 Protein/genetics
• Biomarkers, Tumor/genetics
• Breast Neoplasms/epidemiology
• Breast Neoplasms/genetics
• Breast Neoplasms/pathology
• Case-Control Studies
• DNA Methylation
• Female
• Follow-Up Studies
• Glutathione S-Transferase pi/genetics
• Humans
• Middle Aged
• Prognosis
• Promoter Regions, Genetic
• Tumor Suppressor Proteins/genetics
• Vietnam/epidemiology

This paper describes two different electrochemical affinity biosensing approaches for the simple, fast and bisulfite and PCR-free quantification of 5-methylated cytosines (5-mC) in DNA using the anti-5-mC antibody as biorecognition element. One of the biosensing approaches used the anti-5-mC as capture bioreceptor and a sandwich type immunoassay, while the other one involved the use of a specific DNA probe and the anti-5-mC as a detector bioreceptor of the captured methylated DNA. Both strategies, named for simplicity in the text as immunosensor and DNA sensor, respectively, were implemented on the surface of magnetic microparticles and the transduction was accomplished by amperometry at screen-printed carbon electrodes by means of the hydrogen peroxide/hydroquinone system. The resulting amperometric biosensors demonstrated reproducibility throughout the entire protocol, sensitive determination with no need for using amplification strategies, and competitiveness with the conventional enzyme-linked immunosorbent assay methodology and the few electrochemical biosensors reported so far in terms of simplicity, sensitivity and assay time. The DNA sensor exhibited higher sensitivity and allowed the detection of the gene-specific methylations conversely to the immunosensor, which detected global DNA methylation. In addition, the DNA sensor demonstrated successful applicability for 1 h-analysis of specific methylation in two relevant tumor suppressor genes in spiked biological fluids and in genomic DNA extracted from human glioblastoma cells.

Aberrant epigenetic modifications are an early event in carcinogenesis, with the epigenetic landscape continuing to change during tumor progression and metastasis—these observations suggest that specific epigenetic modifications could be used as diagnostic and prognostic biomarkers for many cancer types. DNA methylation, post-translational histone modifications, and non-coding RNAs are all dysregulated in cancer and are detectable to various degrees in liquid biopsies such as sputum, urine, stool, and blood. Here, we will focus on the application of liquid biopsies, as opposed to tissue biopsies, because of their potential as non-invasive diagnostic tools and possible use in monitoring therapy response and progression to metastatic disease. This includes a discussion of septin-9 (SEPT9) DNA hypermethylation for detecting colorectal cancer, which is by far the most developed epigenetic biomarker assay. Despite their potential as prognostic and diagnostic biomarkers, technical issues such as inconsistent methodology between studies, overall low yield of epigenetic material in samples, and the need for improved histone and non-coding RNA purification methods are limiting the use of epigenetic biomarkers. Once these technical limitations are overcome, epigenetic biomarkers could be used to monitor cancer development, disease progression, therapeutic response, and recurrence across the entire cancer care continuum.

• biomarkers
• cancer
• epigenetics
• liquid biopsy

• Biomarker
• Brain disorders
• Cancer
• DNA methylation
• Epigenetics
• Liquid biopsy
• Molecular diagnosis

• Biomarkers, Tumor/blood
• DNA Methylation/genetics
• Epigenesis, Genetic
• Humans
• Liquid Biopsy
• Neoplasms/blood
• Neoplasms/genetics
• Pathology, Molecular/trends

• P01 NS097206 NINDS NIH HHS
• R01 MH102690 NIMH NIH HHS
• R01 NS051630 NINDS NIH HHS
• R01 NS079625 NINDS NIH HHS

The goal of this study was to develop a method for whole genome cell-free DNA (cfDNA) methylation analysis in humans and mice with the ultimate goal to facilitate the identification of tumor derived DNA methylation changes in the blood. Plasma or serum from patients with pancreatic neuroendocrine tumors or lung cancer, and plasma from a murine model of pancreatic adenocarcinoma was used to develop a protocol for cfDNA isolation, library preparation and whole-genome bisulfite sequencing of ultra low quantities of cfDNA, including tumor-specific DNA. The protocol developed produced high quality libraries consistently generating a conversion rate >98% that will be applicable for the analysis of human and mouse plasma or serum to detect tumor-derived changes in DNA methylation.

• DNA methylation
• biomarker
• cell-free DNA
• cfDNA
• circulating DNA
• mouse cfDNA
• non-invasive blood based screening
• pancreatic cancer

Although increasing numbers of methylated genes have been identified as biomarkers for endometrial cancer, the results have been inconsistent. We therefore carried out a systematic review and meta-analysis to evaluate the diagnostic accuracy of methylated genes as markers for sporadic endometrial cancer.

A total of 22 studies including 1930 participants (sporadic endometrial cancer patients and normal individuals) met our eligibility criteria. The pooled sensitivity and specificity were 0.93 (95% confidence interval: 0.91−0.94) and 0.48 (95% confidence interval: 0.46–0.50), respectively. The area under the summary receiver operating characteristic curve was 0.8834. The presence of DNA methylation was significantly associated with lymph node metastasis of endometrial cancer (pooled odds ratio: 0.28, 95% confidence interval: 0.15–0.52, p < 0.001).

We searched the relevant literature systematically using the PubMed and Web of Science databases up to April 2017. Diagnostic accuracy variables were pooled and analyzed using Meta-DiSc software. Sensitivity analysis and publication bias were evaluated using Review Manager.

This meta-analysis suggests that the detection of DNA methylation is associated with lymph node metastasis, with high sensitivity but relatively low specificity for the diagnosis of sporadic endometrial cancer.

• DNA methylation
• biomarker
• diagnosis
• endometrial cancer
• meta-analysis

• Cell-free DNA
• Chimerism analysis