scholarly journals Identification of Cell-Free DNA Methylation Patterns Unique to the Human Left Ventricle as a Potential Indicator of Acute Cellular Rejection

2021 ◽  
Author(s):  
Sabrina Pattar ◽  
Mohammad Aleinati ◽  
Fatima Iqbal ◽  
Aiswarya Madhu ◽  
Samuel Blais ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Left Ventricle ◽  
Chromosome 9 ◽  
Cell Free Dna ◽  
Promising Alternative ◽  
Non Invasive ◽  
Free Dna ◽  
Cellular Apoptosis ◽  
Human Left Ventricle ◽  
Methylation Patterns

AbstractIncreased levels of donor-derived cell-free DNA (dd-cfDNA) in recipient plasma have been associated with rejection after transplantation. DNA sequence differences have been used to distinguish between donor and recipient but epigenetic differences could also potentially identify dd-cfDNA. This pilot study aimed to identify ventricle-specific differentially methylated regions of DNA (DMRs) that could be detected in cfDNA. We identified 24 ventricle-specific DMRs and chose two for further study, one on chromosome 9 and one on chromosome 12. The specificity of both DMRs for the left ventricle was confirmed using genomic DNA from multiple human tissues. Serial matched samples of myocardium (n=33) and plasma (n=24) were collected from stable adult heart transplant recipients undergoing routine endomyocardial biopsy for rejection surveillance. Plasma DMR levels increased with biopsy-proven rejection grade for individual patients. Mean cellular apoptosis in biopsy samples increased significantly with rejection severity (2.4%, 4.4% and 10.0% for ACR 0R, 1R and 2R, respectively) but did not show a consistent relationship with DMR levels. We identified multiple DNA methylation patterns unique to the human ventricle and conclude that epigenetic differences in cfDNA populations represent a promising alternative strategy for the non-invasive detection of rejection.

scholarly journals Aging-associated distinctive DNA methylation changes of LINE-1 retrotransposons in pure cell-free DNA from human blood

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Wardah Mahmood ◽  
Lars Erichsen ◽  
Pauline Ott ◽  
Wolfgang A. Schulz ◽  
Johannes C. Fischer ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cell Free Dna ◽  
The Past ◽  
Free Dna ◽  
Genome Wide ◽  
Cancerous Cell ◽  
Pure Cell ◽  
Epigenetic Biomarker ◽  
Methylation Patterns ◽  
Cancerous Cells

AbstractLINE-1 hypomethylation of cell-free DNA has been described as an epigenetic biomarker of human aging. However, in the past, insufficient differentiation between cellular and cell-free DNA may have confounded analyses of genome-wide methylation levels in aging cells. Here we present a new methodological strategy to properly and unambiguously extract DNA methylation patterns of repetitive, as well as single genetic loci from pure cell-free DNA from peripheral blood. Since this nucleic acid fraction originates mainly in apoptotic, senescent and cancerous cells, this approach allows efficient analysis of aged and cancerous cell-specific DNA methylation patterns for diagnostic and prognostic purposes. Using this methodology, we observe a significant age-associated erosion of LINE-1 methylation in cfDNA suggesting that the threshold of hypomethylation sufficient for relevant LINE-1 activation and consequential harmful retrotransposition might be reached at higher age. We speculate that this process might contribute to making aging the main risk factor for many cancers.

scholarly journals Detection of glioma and prognostic subtypes by non-invasive circulating cell-free DNA methylation markers

2019 ◽  
Author(s):  
H Noushmehr ◽  
TS Sabedot ◽  
TM Malta ◽  
K Nelson ◽  
J Snyder ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cerebrospinal Fluid ◽  
Tumor Tissue ◽  
Standard Of Care ◽  
Pancreatic Islet Transplantation ◽  
Cell Free Dna ◽  
Non Invasive ◽  
Free Dna ◽  
Genome Wide ◽  
Low Sensitivity

SUMMARYGenome-wide DNA methylation profiling has shown that epigenetic abnormalities are biologically important in glioma and can be used to classify these tumors into distinct prognostic groups. Thus far, DNA profiling has required surgically resected glioma tissue; however, gliomas release tumoral material into biofluids, such as blood and cerebrospinal fluid, providing an opportunity for a minimally invasive testing. While prior studies have shown that genetic and epigenetic markers can be detected in blood or cerebrospinal fluid (e.g., liquid biopsy [LB]), there has been low sensitivity for tumor-specific markers. We hypothesize that the low sensitivity is due to the targeted assay methods. Therefore, we profiled the genome-wide CpG methylation levels in DNA of tumor tissue and cell-free DNA in serum of glioma patients, to identify non-invasive epigenetic LB (eLB) markers in the serum that reflect the characteristics of the tumor tissue. From the epigenetic profiles of serum from patients diagnosed with glioma (N=15IDHmutant and N=7IDHwildtype) and with epilepsy (N=3), we defined glioma-specific andIDH-specific eLB signatures (Glioma-eLB andIDH-eLB, respectively). The epigenetic profiles of the matched tissue demonstrate that these eLB signatures reflected the signature of the tumor. Through cross-validation we show that Glioma-eLB can accurately predict a patient’s glioma from those with other neoplasias (N=6 Colon; N=14 Pituitary; N=3 Breast; N=4 Lung), non-neoplastic immunological conditions (N=22 sepsis; N=9 pancreatic islet transplantation), and from healthy individuals (sensitivity: 98%; specificity: 99%). Finally,IDH-eLB includes promoter methylated markers associated with genes known to be involved in glioma tumorigenesis (PVT1andCXCR6). The application of the non-invasive eLB signature discovered in this study has the potential to complement the standard of care for patients harboring glioma.

Epigenetic biomarkers for noninvasive detection of colorectal cancer.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 45-45
Author(s):  
Dhruvajyoti Roy ◽  
David Taggart ◽  
Lianghong Zheng ◽  
Dan Liu ◽  
Gen Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Methylation ◽  
Stage I ◽  
Cancer Stage ◽  
Cell Free Dna ◽  
Non Invasive ◽  
Epigenetic Biomarkers ◽  
Free Dna ◽  
Diagnostic Potential ◽  
Target Sites

45 Background: Aberrant DNA hypermethylation is known to be a major mechanism for inactivation of cancer-associated genes, including tumor suppressor genes, in colorectal cancer (CRC) and in other human cancers. Cancer-specific DNA methylation patterns of cell-free DNA (cfDNA) isolated from blood samples is a non-invasive method to obtain representative epigenetic information from solid tumors. In the present study, we identified and validated colorectal cancer-specific methylation markers for diagnosis of the disease with high sensitivity and specificity. We also compared the relative amount of DNA methylation at these target sites in relation to colorectal cancer stage. Methods: For marker validation, a total of 154 samples drawn from 68 subjects diagnosed with colorectal cancer (Stage I to IV), 42 healthy donors, 14 subjects with benign colorectal diseases, and 30 subjects diagnosed with other cancer types (breast, liver and lung cancer: 10 cases each) were obtained for a randomized, blinded study. Cell-free DNA was then extracted from the samples, bisulfite converted, and DNA methylation was quantified by using the IvyGene Platform. Results: By quantifying DNA methylation at the target sites, colorectal cancer samples were differentiated from samples drawn from healthy subjects or subjects with benign disease with an overall sensitivity of 93% (95% CI: 86-99) and specificity of 100% (95% CI: 85-100). All stages (I to IV) of colorectal cancer were identified with sensitivities ranging from 67% to 100%. None of the 30 samples drawn from subjects diagnosed with breast, liver or lung cancers were incorrectly identified as a colorectal cancer by the assay, for a calculated analytical specificity of 100%. Conclusions: These results demonstrate the high diagnostic potential of cfDNA methylation markers isolated from blood for the detection of colorectal cancer. Taken together, these findings establish the utility of methylation biomarkers for the detection of colorectal cancers as early as Stage I. In addition, a quantitative analysis of cfDNA provides an opportunity for non-invasive detection and monitoring of disease.

scholarly journals CancerDetector: ultrasensitive and non-invasive cancer detection at the resolution of individual reads using cell-free DNA methylation sequencing data

2018 ◽  
Vol 46 (15) ◽  
pp. e89-e89 ◽  
Author(s):  
Wenyuan Li ◽  
Qingjiao Li ◽  
Shuli Kang ◽  
Mary Same ◽  
Yonggang Zhou ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cancer Detection ◽  
Invasive Cancer ◽  
Sequencing Data ◽  
Cell Free Dna ◽  
Non Invasive ◽  
Free Dna

scholarly journals A serum-based DNA methylation assay provides accurate detection of glioma

2021 ◽  
Author(s):  
Thais Sabedot ◽  
Tathiane Malta ◽  
James Snyder ◽  
Kevin Nelson ◽  
Michael Wells ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Liquid Biopsy ◽  
Somatic Mutations ◽  
Methylation Status ◽  
Experimental Treatment ◽  
Cell Free Dna ◽  
Invasive Approach ◽  
Non Invasive ◽  
Free Dna

Abstract Background The detection of somatic mutations in cell-free DNA (cfDNA) from liquid biopsy has emerged as a non-invasive tool to monitor the follow-up of cancer patients. However, the significance of cfDNA clinical utility remains uncertain in patients with brain tumors, primarily because of the limited sensitivity cfDNA has to detect real tumor-specific somatic mutations. This unresolved challenge has prevented accurate follow-up of glioma patients with non-invasive approaches. Methods Genome-wide DNA methylation profiling of tumor tissue and serum cell-free DNA of glioma patients. Results Here, we developed a non-invasive approach to profile the DNA methylation status in the serum of patients with gliomas and identified a cfDNA-derived methylation signature that is associated with the presence of gliomas and related immune features. By testing the signature in an independent discovery and validation cohorts, we developed and verified a score metric (the “glioma epigenetic liquid biopsy score” or GeLB) that optimally distinguished patients with or without glioma (sensitivity: 100%, specificity: 97.78%). Furthermore, we found that changes in GeLB score reflected clinicopathological changes during surveillance (e.g., progression, pseudoprogression or response to standard or experimental treatment). Conclusions Our results suggest that the GeLB score can be used as a complementary approach to diagnose and follow up patients with glioma.

scholarly journals OS1.5 Detection of glioma and prognostic subtypes by non-invasive circulating cell-free DNA methylation markers

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii6-iii6
Author(s):  
H Noushmehr ◽  
T Sabedot ◽  
T Malta ◽  
K Nelson ◽  
J Snyder ◽  
...  
Keyword(s):  
United States ◽  
Dna Methylation ◽  
Standard Of Care ◽  
United States Department ◽  
Pancreatic Islet Transplantation ◽  
Cell Free Dna ◽  
Non Invasive ◽  
Free Dna ◽  
Genome Wide ◽  
Low Sensitivity

Abstract BACKGROUND: Genome-wide DNA methylation profiling has shown that epigenetic abnormalities are biologically important in glioma and can be used to classify these tumors into distinct prognostic groups. Thus far, DNA profiling has required surgically resected glioma tissue; however, gliomas release tumoral material into biofluids providing an opportunity for a minimally invasive testing. While prior studies have shown that molecular markers can be detected in liquid biopsy (LB), there has been low sensitivity for tumor-specific markers. We hypothesize that the low sensitivity is due to the targeted assay methods. METHODS: Genome-wide CpG methylation levels in DNA of tumor tissue and cell-free DNA serum of glioma patients. RESULTS: We defined glioma-specific and IDH-specific epigenetic LB (eLB) signatures (Glioma-eLB and IDH-eLB, respectively) from serum cell-free DNA from patients diagnosed with glioma (N=15 IDH mutant and N=7 IDH wildtype) and with epilepsy (N=3). The epigenetic profiles of the matched tissue demonstrate that these eLB signatures reflected the signature of the tumor. Through cross-validation we show that Glioma-eLB can accurately predict a patient’s glioma from those with other neoplasias (N=6 Colon; N=14 Pituitary; N=3 Breast; N=4 Lung), non-neoplastic immunological conditions (N=22 sepsis; N=9 pancreatic islet transplantation), and from healthy individuals (sensitivity: 98%; specificity: 99%). Finally, IDH-eLB includes promoter methylated markers associated with genes known to be involved in glioma tumorigenesis (PVT1 and CXCR6). CONCLUSIONS: The application of the non-invasive eLB signature discovered in this study has the potential to complement the standard of care for patients harboring glioma. This project is supported by the Henry Ford Health System, Department of Neurosurgery and the Hermelin Brain Tumor Center Foundation (A30935), United States National Institutes of Health (R01CA222146), and United States Department of Defense (CA170278)

scholarly journals Cancer Detection from Plasma Cell-Free DNA

2020 ◽  
Vol 218 ◽  
pp. 03049
Author(s):  
Li Chen
Keyword(s):  
Cancer Detection ◽  
Feature Fusion ◽  
Detection Methods ◽  
Sequencing Analysis ◽  
Cell Free Dna ◽  
Non Invasive ◽  
Free Dna ◽  
Genome Bisulfite Sequencing ◽  
Number Variation ◽  
Methylation Patterns

Liquid biopsy of cell-free DNA (cfDNA) has attracted much attention for its promise to realize pan-cancer detection in a non-invasive way. The whole-genome bisulfite sequencing (WGBS) is widely used in cfDNA sequencing analysis and lays the foundation for further study on cfDNA. The cfDNA released by multiple tissues carries genetic and epigenetic information. Methylation patterns, copy number variation (CNV) and fragmentation changes have been discovered in previous studies and achieved a promising accuracy. In this review, different cancer detection methods based on these three biomarkers are introduced. In addition, feature fusion is discussed for its potential in enhancing performance in clinical applications.

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