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

Lehmann-Werman, Roni; Neiman, Daniel; Zemmour, Hai; Moss, Joshua; Magenheim, Judith; Vaknin‐Dembinsky, Adi; Rubertsson, Sten; Nellgård, Bengt; Blennow, Kaj; Zetterberg, Henrik; Spalding, Kirsty L.; Haller, Michael J.; Wasserfall, Clive; Schatz, Desmond; Greenbaum, Carla J.; Dorrell, Craig; Grompe, Markus; Zick, Aviad; Hubert, Ayala; Maoz, Myriam; Fendrich, Volker; Bartsch, Detlef K.; Golan, Talia; Sasson, Shmuel A. Ben; Zamir, Gideon; Razin, Aharon; Cedar, Howard; Shapiro, A. M. James; Gläser, Benjamin; Shemer, Ruth; Dor, Yuval

doi:10.1073/pnas.1519286113

Cited by 513 publications

(552 citation statements)

References 51 publications

(39 reference statements)

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“…Through sequencing of bisulfate-converted DNA (bis-DNA), we identified many previously unknown CpG markers differentially methylated in cancer tissues versus normal tissues. LehmannWerman et al (18) described multiple adjacent CpG sites that share the same tissue-specific methylation pattern. We further explored this concept of the mBlock and found that many nearby methylation markers are highly correlated.…”

Section: Discussionmentioning

confidence: 99%

DNA methylation markers for diagnosis and prognosis of common cancers

Hao

Luo

Krawczyk

et al. 2017

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

368

278

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The ability to identify a specific cancer using minimally invasive biopsy holds great promise for improving the diagnosis, treatment selection, and prediction of prognosis in cancer. Using whole-genome methylation data from The Cancer Genome Atlas (TCGA) and machine learning methods, we evaluated the utility of DNA methylation for differentiating tumor tissue and normal tissue for four common cancers (breast, colon, liver, and lung). We identified cancer markers in a training cohort of 1,619 tumor samples and 173 matched adjacent normal tissue samples. We replicated our findings in a separate TCGA cohort of 791 tumor samples and 93 matched adjacent normal tissue samples, as well as an independent Chinese cohort of 394 tumor samples and 324 matched adjacent normal tissue samples. The DNA methylation analysis could predict cancer versus normal tissue with more than 95% accuracy in these three cohorts, demonstrating accuracy comparable to typical diagnostic methods. This analysis also correctly identified 29 of 30 colorectal cancer metastases to the liver and 32 of 34 colorectal cancer metastases to the lung. We also found that methylation patterns can predict prognosis and survival. We correlated differential methylation of CpG sites predictive of cancer with expression of associated genes known to be important in cancer biology, showing decreased expression with increased methylation, as expected. We verified gene expression profiles in a mouse model of hepatocellular carcinoma. Taken together, these findings demonstrate the utility of methylation biomarkers for the molecular characterization of cancer, with implications for diagnosis and prognosis.

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Section: Discussionmentioning

confidence: 99%

DNA methylation markers for diagnosis and prognosis of common cancers

Hao

Luo

Krawczyk

et al. 2017

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

368

278

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“…Single-CTC methylation analysis was recently demonstrated by Huang and colleagues, indicating at a gross level that DNA was hypomethylated and RNA was hypermethylated [162,163]. Along similar lines, methylation patterns in ctDNA has been used to identify tissue-specific cell death [164], and ctDNA detection of aberrant promoter methylation in a six-gene panel has been used for diagnosing breast cancer [165]. Con current multiomics analysis of single CTCs in a highly automated and multiplexed fashion using microfluidics and barcoding technology could augment lineage tracing and dissection of the genetic and epigenetic contributions to CTC cell state and dynamics (via the transcriptome readout) [166].…”

Section: Conclusion and Future Perspectivementioning

confidence: 86%

The Promise of Circulating Tumor Cells for Precision Cancer Therapy

Hwang

Miyamoto

2016

Biomark. Med.

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The rapidly growing array of therapeutic options in cancer requires informative biomarkers to guide the rational selection and precision application of appropriate therapies. Circulating biomarkers such as circulating tumor cells have immense potential as noninvasive, serial 'liquid biopsies' that may be more representative of the complete spectrum of a patient's individual malignancy than spatially and temporally restricted tumor biopsies. In this review, we discuss the current state-of-the-art in the isolation and molecular characterization of circulating tumor cells as well as their utility in a wide range of clinical applications such as prognostics, treatment monitoring and identification of novel therapeutic targets and resistance mechanisms to enable real-time adjustments in the clinical management of cancer. The evolving landscape of cancer therapy creates an urgent need for minimally invasive biomarkers to facilitate early detection, prognosis and prediction of therapeutic response and resistance to enable highly adaptable, real-time precision therapy [1]. The conventional gold standard of using single biopsies of the primary tumor to inform all downstream therapeutic decisions may no longer be adequate given increasing evidence of significant spatial and temporal hetero geneity in tumors [2], especially when placed under the selection pressure of various treatments. Moreover, serial biopsies are often impractical, morbid and technically challenging.In this review, we focus on the emerging role of circulating tumor cells (CTCs), which can be serially obtained from minimally invasive blood draws or 'liquid biopsies'. CTCs are cancer cells that have been shed into the peripheral circulation from primary or metastatic tumors [3,4]. The first reported observation of CTCs was in 1869 by Australian pathologist Thomas Ashworth at the autopsy of a patient with metastatic cancer [5]. By comparing the morphology of circulating cells with those from different cancerous lesions, Ashworth came to the prescient conclusion that 'cells identical with those of the cancer itself being seen in the blood may tend to throw some light upon the mode of origin of multiple tumors existing in the same person' [5]. Indeed, molecular analyses of CTCs may be superior to individual tumor biopsies because these circulating cells likely provide a sampling of different regions of the primary tumor as well as metastatic deposits, and therefore are more likely to capture the genetic heterogeneity of a patient's cancer.While cell-free circulating tumor DNA (ctDNA) is an important, complementary biomarker to CTCs, it has been reviewed extensively elsewhere and will not be discussed in this review [4,6]. Moreover, although ctDNA may in some cases be more reliably [7], they are largely limited to genomic mutational analysis. In contrast, CTC analysis can provide a wealth of other information including cell morphology, immunocytochemical phenotype, presence of important epitopes, presence of multiple mutations within a single cell to decode ...

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“…Hence, each pathologic process associated with tissue damage that leads to the release of tissue-specific ccfDNA can theoretically be measured with ccfDNA methylation analyses. Recently, a proof-of-concept study was published that demonstrated the detection of tissue-specific cell death based on methylation patterns in ccfDNA [23]. This study showed that pancreatic β-cell DNA can be detected in the circulation of patients with diagnosed type-1 diabetes and islet-graft recipients.…”

Section: Other Diseases Beyond Cancermentioning

confidence: 99%

Current status and future perspectives of circulating cell-free DNA methylation in clinical diagnostics

Dietrich

2016

LaboratoriumsMedizin

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Aberrant DNA methylation is a hallmark of malignancies and can be detected in circulating cell-free DNA (ccfDNA) in bodily fluids, i.e. blood plasma, serum and urine. The availability of technologies that allow for an accurate and sensitive quantification of ccfDNA DNA methylation enables the precise monitoring of dynamic pathologic processes and pharmacodynamics. Recently, the first ccfDNA methylation biomarker SEPT9 received clearance by the US Food and Drug Administration (FDA) with its intended use for blood-based colorectal cancer screening. In this review, the application of ccfDNA methylation as a biomarker for diagnosis, screening, early detection, prognosis, molecular staging, therapy response monitoring, and recurrence monitoring is discussed. Special emphasis is placed on the potential and the limitations of methylation biomarkers for the clinical management of prostate, lung, colorectal, bladder, and head and neck cancer. Current and future applications of the validated methylation biomarkers SHOX2 and SEPT9 are highlighted. Additional applications of methylation biomarkers in ccfDNA beyond cancer are discussed briefly. Furthermore, preanalytical and analytical procedures are discussed with regard to a possible implementation of ccfDNA methylation biomarkers into clinical laboratories.

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

Cited by 513 publications

References 51 publications

DNA methylation markers for diagnosis and prognosis of common cancers

DNA methylation markers for diagnosis and prognosis of common cancers

The Promise of Circulating Tumor Cells for Precision Cancer Therapy

Current status and future perspectives of circulating cell-free DNA methylation in clinical diagnostics

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