Novel Methylated Biomarkers and a Robust Assay to Detect Circulating Tumor DNA in Metastatic Breast Cancer

Fackler, Mary Jo; Lopez‐Bujanda, Zoila A.; Umbricht, Christopher B.; Teo, Wei Wen; Cho, Soonweng; Zhang, Zhe; Visvanathan, Kala; Jeter, Stacie C.; Argani, Pedram; Wang, Chenguang; Lyman, Jaclyn P.; Brot, Marina De; Ingle, James N.; Boughey, Judy C.; McGuire, Kandace P.; King, Tari A.; Carey, Lisa A.; Cope, Leslie; Wolff, Antonio C.; Sukumar, Saraswati

doi:10.1158/0008-5472.can-13-3392

Cited by 141 publications

(112 citation statements)

References 32 publications

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“…DNA methylation in cfDNA has been studied extensively but usually in the context of epigenetic aberrations unique to the specific pathology, such as abnormal methylation in promoters of tumor-suppressor genes, which may lead to insights into cancer biology (17)(18)(19)(20). By contrast, our approach seeks to identify, in plasma or serum, the normal, stable methylation signature of a specific tissue as a sensitive biomarker of cell death.…”

Section: Significancementioning

confidence: 99%

Identification of tissue-specific cell death using methylation patterns of circulating DNA

Lehmann-Werman¹,

Neiman²,

Zemmour³

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

504

510

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Minimally invasive detection of cell death could prove an invaluable resource in many physiologic and pathologic situations. Cell-free circulating DNA (cfDNA) released from dying cells is emerging as a diagnostic tool for monitoring cancer dynamics and graft failure. However, existing methods rely on differences in DNA sequences in source tissues, so that cell death cannot be identified in tissues with a normal genome. We developed a method of detecting tissue-specific cell death in humans based on tissue-specific methylation patterns in cfDNA. We interrogated tissue-specific methylome databases to identify cell type-specific DNA methylation signatures and developed a method to detect these signatures in mixed DNA samples. We isolated cfDNA from plasma or serum of donors, treated the cfDNA with bisulfite, PCR-amplified the cfDNA, and sequenced it to quantify cfDNA carrying the methylation markers of the cell type of interest. Pancreatic β-cell DNA was identified in the circulation of patients with recently diagnosed type-1 diabetes and islet-graft recipients; oligodendrocyte DNA was identified in patients with relapsing multiple sclerosis; neuronal/glial DNA was identified in patients after traumatic brain injury or cardiac arrest; and exocrine pancreas DNA was identified in patients with pancreatic cancer or pancreatitis. This proof-of-concept study demonstrates that the tissue origins of cfDNA and thus the rate of death of specific cell types can be determined in humans. The approach can be adapted to identify cfDNA derived from any cell type in the body, offering a minimally invasive window for diagnosing and monitoring a broad spectrum of human pathologies as well as providing a better understanding of normal tissue dynamics.

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Section: Significancementioning

confidence: 99%

Identification of tissue-specific cell death using methylation patterns of circulating DNA

Lehmann-Werman¹,

Neiman²,

Zemmour³

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

504

510

View full text Add to dashboard Cite

show abstract

“…Circulating DNA, miRNA and mRNA in blood may be useful for the detection of various human diseases (19,20). Circulating DNA in blood may be a very promising biomarker for precise diagnosis and treatment for breast cancer (20)(21)(22). Because the amplification of chromosomal 8q24 transcribing PVT1 has been identified in a number of cancers, including breast cancer, thus, we hypothesized that the circulating PVT1 DNA might be a useful marker for filtering breast cancer patients from healthy individuals.…”

Section: Discussionmentioning

confidence: 99%

Amplification and the clinical significance of circulating cell-free DNA of PVT1 in breast cancer

Chen

Wang

et al. 2017

Oncology Reports

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Abstract. Duplication in the chromosome 8q24 region is a frequent occurrence in carcinomas. The PVT1 oncogene (PVT1), a long non-coding RNA, is found in this locus. PVT1 amplification is a frequent event in cancers, such as in lymphomas, serous ovarian, colorectal and breast cancers. Ectopic PVT1 expression is related with reduced survival duration in cancer patients. in the present study, we proved that PVT1 is markedly augmented in breast cancer tissues compared with adjacent non-tumorous tissues. Thus, PVT1 is an independent prognostic factor for the survival duration of breast cancer patients. Furthermore, PVT1 is pivotal in regulating p21 expression. in addition, we detected PVT1 DNA in serum and found that circulating PVT1 DNA significantly increased in the serum of breast cancer patients. Compared with PVT1 RNA, DNA is the main form of the PVT1-derived segment. These relevant findings collectively demonstrate that PVT1 plays a pivotal role in breast cancer and is a possible target for novel breast cancer therapies. The detection of circulating PVT1 DNA fragments may be a convenient means to predict the prognosis of breast cancer patients.

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“…Furthermore, promoter hyper-methylation of breast cancer oncogenes tends to inhibit growth regulatory genes, resulting in irregular cell division, whereas global DNA hypo-methylation can stimulate the expression of metastatic genes that are required for cancer cells dissemination [239]. Recently, a whole genome methylation analysis on cell free circulating DNA detected seven novel markers presenting frequent and high levels of methylation in both ERpositive and ER-negative cancer samples compared with low levels in counterpart normal samples [240]. These markers included AKR2B2, COL6A2, GPX7, HIST1H3C, HOXB4, RASGRF2, and TM6SF1, for which the specificity and sensitivity of the screening analysis has been found to be ~96%.…”

Section: Circadian Disruption Biomarkers In Obesity and Cancer Researchmentioning

confidence: 99%

Artificial light-at-night – a novel lifestyle risk factor for metabolic disorder and cancer morbidity

Zubidat

Haim

2017

Journal of Basic and Clinical Physiology and Pharmacology

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Both obesity and breast cancer are already recognized worldwide as the most common syndromes in our modern society. Currently, there is accumulating evidence from epidemiological and experimental studies suggesting that these syndromes are closely associated with circadian disruption. It has been suggested that melatonin (MLT) and the circadian clock genes both play an important role in the development of these syndromes. However, we still poorly understand the molecular mechanism underlying the association between circadian disruption and the modern health syndromes. One promising candidate is epigenetic modifications of various genes, including clock genes, circadian-related genes, oncogenes, and metabolic genes. DNA methylation is the most prominent epigenetic signaling tool for gene expression regulation induced by environmental exposures, such as artificial light-at-night (ALAN). In this review, we first provide an overview on the molecular feedback loops that generate the circadian regulation and how circadian disruption by ALAN can impose adverse impacts on public health, particularly metabolic disorders and breast cancer development. We then focus on the relation between ALAN-induced circadian disruption and both global DNA methylation and specific loci methylation in relation to obesity and breast cancer morbidities. DNA hypo-methylation and DNA hyper-methylation, are suggested as the most studied epigenetic tools for the activation and silencing of genes that regulate metabolic and monostatic responses. Finally, we discuss the potential clinical and therapeutic roles of MLT suppression and DNA methylation patterns as novel biomarkers for the early detection of metabolic disorders and breast cancer development.

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Novel Methylated Biomarkers and a Robust Assay to Detect Circulating Tumor DNA in Metastatic Breast Cancer

Cited by 141 publications

References 32 publications

Identification of tissue-specific cell death using methylation patterns of circulating DNA

Identification of tissue-specific cell death using methylation patterns of circulating DNA

Amplification and the clinical significance of circulating cell-free DNA of PVT1 in breast cancer

Artificial light-at-night – a novel lifestyle risk factor for metabolic disorder and cancer morbidity

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