scholarly journals 1123O Evaluation of cell-free DNA approaches for multi-cancer early detection

2021 ◽  
Vol 32 ◽  
pp. S921
Author(s):  
M.C. Liu ◽  
A. Jamshidi ◽  
E.A. Klein ◽  
O. Venn ◽  
E. Hubbell ◽  
...  
Keyword(s):  
Early Detection ◽  
Cell Free Dna ◽  
Cancer Early Detection ◽  
Free Dna

scholarly journals Clinical correlates of circulating cell-free DNA tumor fraction

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0256436
Author(s):  
Joerg Bredno ◽  
Jafi Lipson ◽  
Oliver Venn ◽  
Alexander M. Aravanis ◽  
Arash Jamshidi
Keyword(s):  
Colorectal Cancer ◽  
Early Detection ◽  
Metabolic Activity ◽  
Linear Models ◽  
Circulating Tumor Dna ◽  
Cell Free Dna ◽  
Clinical Correlates ◽  
Cancer Early Detection ◽  
Free Dna ◽  
Tumor Dna

Background Oncology applications of cell-free DNA analysis are often limited by the amount of circulating tumor DNA and the fraction of cell-free DNA derived from tumor cells in a blood sample. This circulating tumor fraction varies widely between individuals and cancer types. Clinical factors that influence tumor fraction have not been completely elucidated. Methods and findings Circulating tumor fraction was determined for breast, lung, and colorectal cancer participant samples in the first substudy of the Circulating Cell-free Genome Atlas study (CCGA; NCT02889978; multi-cancer early detection test development) and was related to tumor and patient characteristics. Linear models were created to determine the influence of tumor size combined with mitotic or metabolic activity (as tumor mitotic volume or excessive lesion glycolysis, respectively), histologic type, histologic grade, and lymph node status on tumor fraction. For breast and lung cancer, tumor mitotic volume and excessive lesion glycolysis (primary lesion volume scaled by percentage positive for Ki-67 or PET standardized uptake value minus 1.0, respectively) were the only statistically significant covariates. For colorectal cancer, the surface area of tumors invading beyond the subserosa was the only significant covariate. The models were validated with cases from the second CCGA substudy and show that these clinical correlates of circulating tumor fraction can predict and explain the performance of a multi-cancer early detection test. Conclusions Prognostic clinical variables, including mitotic or metabolic activity and depth of invasion, were identified as correlates of circulating tumor DNA by linear models that relate clinical covariates to tumor fraction. The identified correlates indicate that faster growing tumors have higher tumor fractions. Early cancer detection from assays that analyze cell-free DNA is determined by circulating tumor fraction. Results support that early detection is particularly sensitive for faster growing, aggressive tumors with high mortality, many of which have no available screening today.

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 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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