Unknown,Transcriptomics,Genomics,Proteomics

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Detection of hypermethylated circulating serum DNA in metastatic breast cancer and confirmation by the cMethDNA assay

ABSTRACT: The ability to consistently detect cell-free tumor-specific DNA in peripheral blood of patients with metastatic breast cancer provides the opportunity to detect changes in tumor burden and to monitor response to treatment. We developed cMethDNA, a quantitative multiplexed methylation specific PCR assay for a panel of ten genes, discovered through whole genome methylation array analysis of serum DNA. Cancer-specific methylated DNA was detected in training and test sets of recurrent Stage 4 patient sera with a sensitivity of >90% and a specificity of >96%. A core methylation signature was retained in serum, primary and metastatic tissues throughout the course of the disease, and the cMethDNA assay levels reflected patient response to chemotherapy. Together, our data suggest that the cMethDNA assay can provide a sensitive tool to detect minute levels of tumor DNA present in a vast excess of normal DNA in serum. Samples used: 11 cancer sera,,4 pools of normal leukocytes (5 donors per pool), 6 normal breast tissues microdissected, adjacent to tumor, 15 normal breast tissues, organoid preparations

ORGANISM(S): Homo sapiens

SUBMITTER: leslie cope

PROVIDER: E-GEOD-52621 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Increasing evidence has demonstrated that epigenetic factors can profoundly influence gene expression and, in turn, influence resistance or susceptibility to disease. Epigenetic drugs, such as histone deacetylase (HDAC) inhibitors, are finding their way into clinical practice, although their exact mechanisms of action are unclear. To identify mechanisms associated with HDAC inhibition, we performed microarray analysis on brain and muscle samples treated with the HDAC1/3-targeting inhibitor, HDACi 4b. Pathways analyses of microarray datasets implicate DNA methylation as significantly associated with HDAC inhibition. Further assessment of DNA methylation changes elicited by HDACi 4b in human fibroblasts from normal controls and patients with Huntington's disease (HD) using the Infinium HumanMethylation450 BeadChip revealed a limited, but overlapping, subset of methylated CpG sites that were altered by HDAC inhibition in both normal and HD cells. Among the altered loci of Y chromosome-linked genes, KDM5D, which encodes Lys (K)-specific demethylase 5D, showed increased methylation at several CpG sites in both normal and HD cells, as well as in DNA isolated from sperm from drug-treated male mice. Further, we demonstrate that first filial generation (F1) offspring from drug-treated male HD transgenic mice show significantly improved HD disease phenotypes compared with F1 offspring from vehicle-treated male HD transgenic mice, in association with increased Kdm5d expression, and decreased histone H3 Lys4 (K4) (H3K4) methylation in the CNS of male offspring. Additionally, we show that overexpression of Kdm5d in mutant HD striatal cells significantly improves metabolic deficits. These findings indicate that HDAC inhibitors can elicit transgenerational effects, via cross-talk between different epigenetic mechanisms, to have an impact on disease phenotypes in a beneficial manner. Bisulphite converted DNA from the 12 samples were hybridised to the Illumina Infinium 27k Human Methylation Beadchip v1.2. We demonstrate that histone deacetylase (HDAC) inhibition can elicit changes in DNA methylation in Huntington’s disease (HD) human fibroblasts, as well as in sperm from HD transgenic mice, in association with DNA methylation-related gene expression changes. We suggest that alterations in sperm DNA methylation lead to transgenerational effects, and, accordingly, we show that first filial generation (F1) offspring of HDAC inhibitor-treated male HD transgenic mice show improved HD disease phenotypes compared with F1 offspring from vehicle-treated male HD transgenic mice. These findings have significant implications for human health because they enforce the concept that ancestral drug exposure may be a major molecular factor that can affect disease phenotypes, yet in a positive manner. Further, we implicate Lys (K)-specific demethylase 5d expression in this phenomenon.

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Detection of hypermethylated circulating serum DNA in metastatic breast cancer and confirmation by the cMethDNA assay

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