scholarly journals Discovery and validation of methylation signatures in circulating cell-free DNA for early detection of esophageal cancer: a case-control study

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Guibin Qiao ◽  
Weitao Zhuang ◽  
Bo Dong ◽  
Chengcheng Li ◽  
Jiayue Xu ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Early Detection ◽  
Esophageal Disease ◽  
Esophageal Tumor ◽  
Healthy Controls ◽  
Esophageal Diseases ◽  
Cell Free Dna ◽  
Free Dna ◽  
Methylation Patterns ◽  
Control Study

Abstract Background Plasma cell-free DNA (cfDNA) methylation has shown promising results in the early detection of multiple cancers recently. Here, we conducted a study to investigate the performance of cfDNA methylation in the early detection of esophageal cancer (ESCA). Methods Specific methylation markers for ESCA were identified and optimized based on esophageal tumor and paired adjacent tissues (n = 24). Age-matched participants with ESCA (n = 85), benign esophageal diseases (n = 10), and healthy controls (n = 125) were randomized into the training and test sets to develop a classifier to differentiate ESCA from healthy controls and benign esophageal disease. The classifier was further validated in an independent plasma cohort of ESCA patients (n = 83) and healthy controls (n = 98). Results In total, 921 differentially methylated regions (DMRs) between tumor and adjacent tissues were identified. The early detection classifier based on those DMRs was first developed and tested in plasma samples, discriminating ESCA patients from benign and healthy controls with a sensitivity of 76.2% (60.5–87.9%) and a specificity of 94.1% (85.7–98.4%) in the test set. The performance of the classifier was consistent irrespective of sex, age, and pathological diagnosis (P > 0.05). In the independent plasma validation cohort, similar performance was observed with a sensitivity of 74.7% (64.0–83.6%) and a specificity of 95.9% (89.9–98.9%). Sensitivity for stage 0–II was 58.8% (44.2–72.4%). Conclusion We demonstrated that the cfDNA methylation patterns could distinguish ESCAs from healthy individuals and benign esophageal diseases with promising sensitivity and specificity. Further prospective evaluation of the classifier in the early detection of ESCAs in high-risk individuals is warranted.

Discovery and validation of methylation signatures in circulating cell-free DNA for early detection of esophageal cancer: A case-control study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16027-e16027
Author(s):  
Weitao Zhuang ◽  
Xiao-song Ben ◽  
Chengcheng Li ◽  
Jiayue Xu ◽  
Dan Tian ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Early Detection ◽  
Methylation Level ◽  
Early Stage ◽  
Precancerous Lesions ◽  
Esophageal Disease ◽  
Esophageal Tumor ◽  
Esophageal Diseases ◽  
Circulating Free Dna ◽  
Free Dna

e16027 Background: The pivotal goal of esophageal cancer (ESCA) screening is to identify early-stage cancer or precancerous lesions when curable treatments are available. Methylation of circulating-free DNA (cfDNA) has shown promising results in the early detection of multiple tumors recently. Here we conducted a prospective study to investigate the performance of cfDNA methylation in the early detection of ESCA. Methods: Specific methylation markers for ESCA were identified and optimized based on 24 esophageal tumor and its corresponding adjacent tissues. Age-matched participants with ESCA (n = 136), benign esophageal disease (n = 21) and healthy controls (n = 126) were randomized into the training and testing sets to develop an early-detection classifier. Results: In total, 921 differentiated methylation blocks (DMBs) between tumor and adjacent tissues were identified, of which 679 (73.7%) showed higher methylation level and 242 (26.3%) had lower methylation level in tumor tissues. In the training set, the specificity of the model built with these DMBs was 94.1% (95% CI, 85.5%−98.4%) and the sensitivity was 86.0% (95% CI, 72.2%−94.8%). The sensitives increased with stages, which were 77.8% (95% CI, 39.8%−97.2%), 90.9% (95% CI, 58.7%−99.8%), 83.3% (95% CI, 51.7%−97.9%) and 100.0% (95%CI, 63.1%−100.0%) for stage I-IV, respectively. Similar results were observed in the testing set with area under curve (AUC) of 0.932 (95% CI, 0.887−0.977). Conclusions: The cfDNA methylation profiles distinguished ESCAs from healthy individuals and benign esophageal diseases with promising sensitivity and specificity. Consideration of the potential value of early detection in ESCAs, further evaluation in larger prospective studies is warranted.

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.

Methylation of FBN1, SPG20, ITF2, RUNX3, SNCA, MLH1, and SEPT9 genes in circulating cell-free DNA as biomarkers of colorectal cancer

2021 ◽  
pp. 1-30
Author(s):  
Maryam Alizadeh-Sedigh ◽  
Mohammad Sadegh Fazeli ◽  
Habibollah Mahmoodzadeh ◽  
Shahin Behrouz Sharif ◽  
Ladan Teimoori-Toolabi
Keyword(s):  
Colorectal Cancer ◽  
Early Detection ◽  
Diagnostic Performance ◽  
Methylation Status ◽  
Melting Curve ◽  
Melting Curve Analysis ◽  
Promoter Regions ◽  
Cell Free Dna ◽  
Free Dna ◽  
Tumor Tissues

BACKGROUND: Investigating aberrant tumor-specific methylation in plasma cell-free DNA provides a promising and noninvasive biomarker for cancer detection. OBJECTIVE: We aimed to investigate methylation status of some promoter regions in the plasma and tumor tissues to find biomarkers for early detection of colorectal cancer. METHODS: This case-control study on seventy colorectal cancer patients and fifty matched healthy controls used Methylation-Specific High-Resolution Melting Curve analysis to evaluate the methylation of the selected promoter regions in converted genomic tissue DNA and plasma cfDNA. RESULTS: The methylation levels in selected regions of SPG20 (+24375 to +24680, +24209 to +24399, and +23625 to +23883), SNCA (+807 to +1013, +7 to +162, and -180 to +7), FBN1 (+223 to +429, +1 to +245, and -18 to -175), ITF2 (+296 to +436 and -180 to +55), SEPT9 (-914412 to -91590 and -99083 to -92264), and MLH1 (-13 to +22) were significantly higher in tumor tissues compared with normal adjacent tissues. The methylation levels of FBN1, ITF2, SNCA, and SPG20 promoters were significantly higher in the patient’s plasma compared to patient’s normal tissue and plasma of healthy control subjects. FBN1, SPG20, and SEPT9 promoter methylation had a good diagnostic performance for discriminating CRC tissues from normal adjacent tissues (AUC > 0.8). A panel of SPG20, FBN1, and SEPT9 methylation had a higher diagnostic value than that of any single biomarker and other panels in tissue-based assay (AUC > 0.9). The methylation of FBN1(a) and SPG20(a) regions, as the closest region to the first coding sequence (CDS), had a good diagnostic performance in plasma cfDNA (AUC > 0.8) while a panel consisted of FBN1(a) and SPG20(a) regions showed excellent diagnostic performance for CRC detection in plasma cfDNA (AUC > 0.9). CONCLUSION: Methylation of FBN1(a) and SPG20(a) promoter regions in the plasma cfDNA can be an excellent simple, non-invasive blood-based test for early detection of CRC.

EpiPanGI Dx: A cell-free DNA methylation fingerprint for the early detection of gastrointestinal cancers

2021 ◽  
pp. clincanres.1982.2021
Author(s):  
Raju Kandimalla ◽  
Jianfeng Xu ◽  
Alexander Link ◽  
Takatoshi Matsuyama ◽  
Kensuke Yamamura ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Early Detection ◽  
Gastrointestinal Cancers ◽  
Cell Free Dna ◽  
Free Dna ◽  
A Cell

scholarly journals Probing of breast cancer using a combination of plasma and urinary circulating cell-free DNA

2020 ◽  
Vol 40 (11) ◽  
Author(s):  
Zhigang Zuo ◽  
Jiying Tang ◽  
Xiaojun Cai ◽  
Feng Ke ◽  
Zhenzong Shi
Keyword(s):  
Breast Cancer ◽  
Early Stage ◽  
Pik3ca Mutation ◽  
Early Stage Breast Cancer ◽  
Healthy Controls ◽  
Cell Free Dna ◽  
Clinical Sensitivity ◽  
Free Dna ◽  
Urine Specimens ◽  
Circulating Cell Free Dna

Abstract Monitoring of early-stage breast cancer is critical in promptly addressing disease relapse. Circulating cell-free DNA provides a minimally invasive and sensitive means to probing the disease. In a longitudinal analysis of 250 patients with early breast cancer, we compared the circulating cell-free DNA recovered from both plasma and urine specimens. For comparison, 50 healthy controls were also recruited. Specific mutations associated with the disease were profiled to determine the clinical sensitivity and specificity. Correlations of recovered concentrations of cell-free DNA with outcomes were examined to address early prognostication. PIK3CA mutation profiling in both plasma and urinary cell-free DNA showed an agreement of 97.2% compared with the results obtained for tumor tissues. The analysis of healthy controls revealed that cell-free DNA measurements were stable and consistent over time. Over the short 6-month period of monitoring, our analyses showed declines in recovered cell-free DNA; these findings may aid physicians in stratifying patients at higher risk for relapse. Similar results were observed in both plasma and urine specimens (hazard ratios: 2.16 and 2.48, respectively). Cell-free DNA presents a novel and sensitive method for the monitoring of early-stage breast cancer. In the present study, serial measurements of both plasma and urine specimens were useful in probing the disease.

scholarly journals Cell-Free DNA Methylation of Selected Genes Allows for Early Detection of the Major Cancers in Women

2018 ◽  
Author(s):  
Carmen Jeronimo ◽  
Sandra Nunes ◽  
Catarina Moreira-Barbosa ◽  
Sofia Salta ◽  
Susana Palma de Sousa ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Early Detection ◽  
Cell Free Dna ◽  
Free Dna

scholarly journals Early Detection of Metastatic Relapse and Monitoring of Therapeutic Efficacy by Ultra-Deep Sequencing of Plasma Cell-Free DNA in Patients With Urothelial Bladder Carcinoma

2019 ◽  
Vol 37 (18) ◽  
pp. 1547-1557 ◽  
Author(s):  
Emil Christensen ◽  
Karin Birkenkamp-Demtröder ◽  
Himanshu Sethi ◽  
Svetlana Shchegrova ◽  
Raheleh Salari ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Early Detection ◽  
Risk Stratification ◽  
Deep Sequencing ◽  
Therapeutic Efficacy ◽  
Patient Specific ◽  
Cell Free Dna ◽  
Free Dna ◽  
Metastatic Relapse ◽  
Ctdna Analysis

PURPOSE Novel sensitive methods for early detection of relapse and for monitoring therapeutic efficacy may have a huge impact on risk stratification, treatment, and ultimately outcome for patients with bladder cancer. We addressed the prognostic and predictive impact of ultra-deep sequencing of cell-free DNA in patients before and after cystectomy and during chemotherapy. PATIENTS AND METHODS We included 68 patients with localized advanced bladder cancer. Patient-specific somatic mutations, identified by whole-exome sequencing, were used to assess circulating tumor DNA (ctDNA) by ultra-deep sequencing (median, 105,000×) of plasma DNA. Plasma samples (n = 656) were procured at diagnosis, during chemotherapy, before cystectomy, and during surveillance. Expression profiling was performed for tumor subtype and immune signature analyses. RESULTS Presence of ctDNA was highly prognostic at diagnosis before chemotherapy (hazard ratio, 29.1; P = .001). After cystectomy, ctDNA analysis correctly identified all patients with metastatic relapse during disease monitoring (100% sensitivity, 98% specificity). A median lead time over radiographic imaging of 96 days was observed. In addition, for high-risk patients (ctDNA positive before or during treatment), the dynamics of ctDNA during chemotherapy was associated with disease recurrence ( P = .023), whereas pathologic downstaging was not. Analysis of tumor-centric biomarkers showed that mutational processes (signature 5) were associated with pathologic downstaging ( P = .024); however, no significant correlation for tumor subtypes, DNA damage response mutations, and other biomarkers was observed. Our results suggest that ctDNA analysis is better associated with treatment efficacy compared with other available methods. CONCLUSION ctDNA assessment for early risk stratification, therapy monitoring, and early relapse detection in bladder cancer is feasible and provides a basis for clinical studies that evaluate early therapeutic interventions.

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