Heterogeneous tumor clones as an explanation of discordance between plasma DNA and tumor DNA alterations

2001 ◽  
Vol 31 (3) ◽  
pp. 300-301 ◽  
Author(s):  
Jose M. Garcia ◽  
Jose M. Silva ◽  
Gemma Dominguez ◽  
Javier Silva ◽  
Felix Bonilla
Keyword(s):  
Plasma Dna ◽  
Dna Alterations ◽  
Tumor Dna ◽  
Heterogeneous Tumor

scholarly journals Clinical Utility of Circulating Tumor DNA in Advanced Rare Cancers

2021 ◽  
Vol 11 ◽  
Author(s):  
Hitomi Sumiyoshi Okuma ◽  
Kan Yonemori ◽  
Yuki Kojima ◽  
Maki Tanioka ◽  
Kazuki Sudo ◽  
...  
Keyword(s):  
Treatment Options ◽  
Circulating Tumor Dna ◽  
Resistance Mutations ◽  
Plasma Dna ◽  
Invasive Approach ◽  
Therapeutic Implications ◽  
Non Invasive ◽  
Rare Cancers ◽  
Dna Alterations ◽  
Tumor Dna

PurposePatients with advanced/relapsed rare cancers have few treatment options. Analysis of circulating tumor DNA in plasma may identify actionable genomic biomarkers using a non-invasive approach.Patients and MethodsRare cancer patients underwent prospective plasma-based NGS testing. Tissue NGS to test concordance was also conducted. Plasma DNA alterations were assessed for incidence, functional impact, therapeutic implications, correlation to survival, and comparison with tissue NGS.ResultsNinety-eight patients were analyzed. Diseases included soft-tissue sarcoma, ovarian carcinoma, and others. Mean turn-around-time for results was 9.5 days. Seventy-six patients had detectable gene alterations in plasma, with a median of 2.8 alterations/patient. Sixty patients had a likely pathogenic alteration. Five received matched-therapy based on plasma NGS results. Two developed known resistance mutations while on targeted therapy. Patients with an alteration having VAF ≥5% had a significantly shorter survival compared to those of lower VAF. Tissue NGS results from eleven of 22 patients showed complete or partial concordance with plasma NGS.ConclusionPlasma NGS testing is less invasive and capable of identifying alterations in advanced rare cancers in a clinically meaningful timeframe. It should be further studied as a prospective enrollment assay in interventional studies for patients with rare advanced stage cancers.Clinical Registration[https://www.umin.ac.jp/ctr/index-j.htm], identifier UMIN000034394.

scholarly journals Preferred end coordinates and somatic variants as signatures of circulating tumor DNA associated with hepatocellular carcinoma

2018 ◽  
Vol 115 (46) ◽  
pp. E10925-E10933 ◽  
Author(s):  
Peiyong Jiang ◽  
Kun Sun ◽  
Yu K. Tong ◽  
Suk Hang Cheng ◽  
Timothy H. T. Cheng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Peripheral Circulation ◽  
Sequence Information ◽  
Sequencing Analysis ◽  
Plasma Samples ◽  
Dna Molecules ◽  
Plasma Dna ◽  
Cell Free Dna ◽  
Free Dna ◽  
Tumor Dna

Circulating tumor-derived cell-free DNA (ctDNA) analysis offers an attractive noninvasive means for detection and monitoring of cancers. Evidence for the presence of cancer is dependent on the ability to detect features in the peripheral circulation that are deemed as cancer-associated. We explored approaches to improve the chance of detecting the presence of cancer based on sequence information present on ctDNA molecules. We developed an approach to detect the total pool of somatic mutations. We then investigated if there existed a class of ctDNA signature in the form of preferred plasma DNA end coordinates. Cell-free DNA fragmentation is a nonrandom process. Using plasma samples obtained from liver transplant recipients, we showed that liver contributed cell-free DNA molecules ended more frequently at certain genomic coordinates than the nonliver-derived molecules. The abundance of plasma DNA molecules with these liver-associated ends correlated with the liver DNA fractions in the plasma samples. Studying the DNA end characteristics in plasma of patients with hepatocellular carcinoma and chronic hepatitis B, we showed that there were millions of tumor-associated plasma DNA end coordinates in the genome. Abundance of plasma DNA molecules with tumor-associated DNA ends correlated with the tumor DNA fractions even in plasma samples of hepatocellular carcinoma patients that were subjected to shallow-depth sequencing analysis. Plasma DNA end coordinates may therefore serve as hallmarks of ctDNA that could be sampled readily and, hence, may improve the cost-effectiveness of liquid biopsy assessment.

scholarly journals Analysis of fragment ends in plasma DNA from patients with cancer

2021 ◽  
Author(s):  
Karan K. Budhraja ◽  
Bradon R. McDonald ◽  
Michelle D. Stephens ◽  
Tania Contente-Cuomo ◽  
Havell Markus ◽  
...  
Keyword(s):  
Nucleotide Sequence ◽  
Characteristic Curve ◽  
Cost Effective ◽  
Cancer Diagnostics ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Plasma Dna ◽  
Patients With Cancer ◽  
Fragmentation Patterns ◽  
Tumor Dna

AbstractFragmentation patterns observed in plasma DNA reflect chromatin accessibility in contributing cells. Since DNA shed from cancer cells and blood cells may differ in fragmentation patterns, we investigated whether analysis of genomic positioning and nucleotide sequence at fragment ends can reveal the presence of tumor DNA in blood and aid cancer diagnostics. We analyzed whole genome sequencing data from >2700 plasma DNA samples including healthy individuals and patients with 11 different cancer types. We observed higher fractions of fragments with aberrantly positioned ends in patients with cancer, driven by contribution of tumor DNA into plasma. Genomewide analysis of fragment ends using machine learning showed overall area under the receiver operative characteristic curve of 0.96 for detection of cancer. Our findings remained robust with as few as 1 million fragments analyzed per sample, suggesting that analysis of fragment ends can become a cost-effective and accessible approach for cancer detection and monitoring.One-sentence summaryAnalyzing the positioning and nucleotide sequence at fragment ends in plasma DNA may enable cancer diagnostics.

Treatment and relapse in breast cancer show significant correlations to noninvasive testing using urinary and plasma DNA

2020 ◽  
Vol 16 (13) ◽  
pp. 849-858
Author(s):  
Jinling Zhang ◽  
Xueli Zhang ◽  
Shuwei Shen
Keyword(s):  
Breast Cancer ◽  
Circulating Tumor Dna ◽  
Noninvasive Testing ◽  
Plasma Dna ◽  
Operating Characteristics ◽  
Risk Profiling ◽  
Routine Monitoring ◽  
Plasma And Urine Samples ◽  
Serial Time Point ◽  
Tumor Dna

Aim: Circulating tumor DNA is promising for routine monitoring of breast cancer. Noninvasive testing allows regular probing using plasma and urine samples. Methods: Peripheral blood and simultaneous urine collection from patients were quantified. Concordance between methods were made. Serial time-point measurements were correlated to disease outcome. Results: Index measurements demonstrate over 90% concordance with biopsy. Receiver operating characteristics curves showed over 0.95 for both plasma and urine results comparing with controls. Patients with lower risk of relapse experienced greater declines in detected DNA levels. Maximal declines were registered at 4.0- and 6.8-fold for plasma and urine results, respectively. Conclusion: Measuring and monitoring DNA levels complement existing testing regimes and provides better risk profiling of patients for possible relapse.

scholarly journals Detection of Circulating Tumor DNA in Patients With Uterine Leiomyomas

2019 ◽  
pp. 1-9
Author(s):  
Joanna Przybyl ◽  
Lien Spans ◽  
Deirdre A. Lum ◽  
Shirley Zhu ◽  
Sujay Vennam ◽  
...  
Keyword(s):  
Lactate Dehydrogenase ◽  
Tumor Suppressor Genes ◽  
Uterine Leiomyoma ◽  
Benign Lesion ◽  
Point Mutations ◽  
Circulating Tumor Dna ◽  
Copy Number Alterations ◽  
Plasma Dna ◽  
Tumor Dna ◽  
Targeted Detection

PURPOSE The preoperative distinction between uterine leiomyoma (LM) and leiomyosarcoma (LMS) is difficult, which may result in dissemination of an unexpected malignancy during surgery for a presumed benign lesion. An assay based on circulating tumor DNA (ctDNA) could help in the preoperative distinction between LM and LMS. This study addresses the feasibility of applying the two most frequently used approaches for detection of ctDNA: profiling of copy number alterations (CNAs) and point mutations in the plasma of patients with LM. PATIENTS AND METHODS By shallow whole-genome sequencing, we prospectively examined whether LM-derived ctDNA could be detected in plasma specimens of 12 patients. Plasma levels of lactate dehydrogenase, a marker suggested for the distinction between LM and LMS by prior studies, were also determined. We also profiled 36 LM tumor specimens by exome sequencing to develop a panel for targeted detection of point mutations in ctDNA of patients with LM. RESULTS We identified tumor-derived CNAs in the plasma DNA of 50% (six of 12) of patients with LM. The lactate dehydrogenase levels did not allow for an accurate distinction between patients with LM and patients with LMS. We identified only two recurrently mutated genes in LM tumors ( MED12 and ACLY). CONCLUSION Our results show that LMs do shed DNA into the circulation, which provides an opportunity for the development of ctDNA-based testing to distinguish LM from LMS. Although we could not design an LM-specific panel for ctDNA profiling, we propose that the detection of CNAs or point mutations in selected tumor suppressor genes in ctDNA may favor a diagnosis of LMS, since these genes are not affected in LM.

Circulating tumor DNA in plasma of breast cancer patients from India

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22213-e22213
Author(s):  
S. Bhattacharyya ◽  
V. Raina ◽  
N. K. Shukla ◽  
S. Shukla ◽  
R. Kumar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Early Diagnosis ◽  
Cancer Patients ◽  
Circulating Tumor Dna ◽  
Genome Equivalent ◽  
Breast Cancer Patients ◽  
Plasma Dna ◽  
Dna Concentration ◽  
Free Plasma ◽  
Tumor Dna

e22213 Background: Recently, breast cancer has become the most common cancer among women in all urban population in India. Annually about 80000 new cases and 40000 deaths occur and majority of breast cancers are pre-menopausal. Conventional diagnostic methods are not very sensitive especially in early stages of cancer. This necessitated a more sensitive and reliable method for early diagnosis leading to effective treatment, better prognosis and survival. Recently, the level of cell free circulating tumor DNA in blood plasma or serum of patients with variety of tumors are being considered as reliable non-invasive diagnostic tool but no study has been done in India. The present study has therefore been undertaken to evaluate clinical utility of cell free DNA as potential biomarkers for early diagnosis and management of breast cancer. Methods: 25 newly diagnosed untreated breast cancer patients and 25 healthy subjects having no sign of significant medical illness with informed consent were enrolled for the study. 9 patients after chemotherapy were also included in the study. Blood plasma collected from both patients and controls were employed for DNA isolation, using Qiagen kit. Concentration of cell free plasma DNA was analyzed by 3 methods viz. nanodrop spectro-photometry, integrated density value (IDV) of PCR products of Exon 7 of p53 gene and quantitative real time PCR (cycles threshold converted to genome equivalent). All values of DNA concentration obtained by three methods used as continuous variables and receiver operating characteristic (ROC) were plotted and the cut-of value was determined at 90% sensitivity and 100% specificity level of ROC. Results: Mean free plasma DNA concentration as determined by both Q-RT PCR and IDV in cancer patients was found to be significantly higher in advanced stage breast cancer patients than in controls (genome equivalent 18850 vs 431; IDV 17912 vs 4197; p=0.001). However, no significant difference could be observed in early stage disease as compared to controls possibly due small sample size. Conclusions: Free Plasma DNA concentration is a reliable molecular marker for detection of breast cancer and can serve as a prognostic indicator leading to its potential clinical application either alone or in combination with other conventional methods. No significant financial relationships to disclose.

scholarly journals Circulating Tumor DNA as a Liquid Biopsy for Cancer

2015 ◽  
Vol 61 (1) ◽  
pp. 112-123 ◽  
Author(s):  
Ellen Heitzer ◽  
Peter Ulz ◽  
Jochen B Geigl
Keyword(s):  
Liquid Biopsy ◽  
Dna Analysis ◽  
Clonal Evolution ◽  
Cost Effective ◽  
Circulating Tumor Dna ◽  
Analytical Sensitivity ◽  
Plasma Dna ◽  
Multicenter Studies ◽  
Almost All ◽  
Tumor Dna

Abstract BACKGROUND Targeted therapies have markedly changed the treatment of cancer over the past 10 years. However, almost all tumors acquire resistance to systemic treatment as a result of tumor heterogeneity, clonal evolution, and selection. Although genotyping is the most currently used method for categorizing tumors for clinical decisions, tumor tissues provide only a snapshot, or are often difficult to obtain. To overcome these issues, methods are needed for a rapid, cost-effective, and noninvasive identification of biomarkers at various time points during the course of disease. Because cell-free circulating tumor DNA (ctDNA) is a potential surrogate for the entire tumor genome, the use of ctDNA as a liquid biopsy may help to obtain the genetic follow-up data that are urgently needed. CONTENT This review includes recent studies exploring the diagnostic, prognostic, and predictive potential of ctDNA as a liquid biopsy in cancer. In addition, it covers biological and technical aspects, including recent advances in the analytical sensitivity and accuracy of DNA analysis as well as hurdles that have to be overcome before implementation into clinical routine. SUMMARY Although the analysis of ctDNA is a promising area, and despite all efforts to develop suitable tools for a comprehensive analysis of tumor genomes from plasma DNA, the liquid biopsy is not yet routinely used as a clinical application. Harmonization of preanalytical and analytical procedures is needed to provide clinical standards to validate the liquid biopsy as a clinical biomarker in well-designed and sufficiently powered multicenter studies.

Chemotherapy induces microssatelite instability (MIS) in plasma free DNA (pfDNA), peripheral blood mononuclear fraction (PBMNF) cells, and urine free DNA (ufDNA) of breast cancer (BC) patients as well as in normal PBMNF cells in vitro in the absence of amifostine (A)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e11505-e11505
Author(s):  
A. Del Giglio ◽  
J. F. Pinto ◽  
F. A. Fonseca ◽  
S. R. Marsicano ◽  
P. O. Delgado ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Plasma Dna ◽  
Peripheral Blood Mononuclear ◽  
Agent Based ◽  
In Vitro Methods ◽  
Free Dna ◽  
Untreated Female ◽  
Tumor Dna ◽  
Mcf 7

e11505 Background: We have previously shown that alkylating agent based chemotherapy regimens (AQT) could induce MIS in the PBMNF of BC patients in parallel to a decrease in the expression of the protein hMSH2 in these cells (Fonseca et al., 2005, Breast Cancer Res, 7, R28–32). Since plasma DNA derives mainly from tumor cells, we wanted to know if chemotherapy would also produce MIS in tumor DNA and if this phenomenon could be reproduced in vitro. Methods: 33 previously untreated female BC patients with a mean age of 51 years received AQT(16 ACT;3FAC;2 TAC;1FEC;10AC). Samples from 3 additional patients who received Fulvestrant only as neoadjuvant therapy were also included. Blood (pfDNA and PBMNNF) and urine (ufDNA) were evaluated at time 0,3 and 6 months with 6 MIS markers (BAT40,BAT26, MR2,TP53 PCR15.1, APC and ALU). Levels of fpDNA and fuDNA were measured by spectrophotometry. We incubated in vitro cultures of MCF- 7 cells and PBMNF cells with M at a dose of 0.7μg/ml for 30 minutes with and without A at 20% of the M dose and evaluated serially for 48 hours for MIS and hMH2 expression by immunohistochemistry. Results: We observed at least one MIS event in the PBMNF, fpDNA or fuDNA in 87%, 80% and 80% of the patients, respectively, mainly in BAT40 and BAT 26 markers. There was only 14.74% of concordance of MIS alterations between PBMNF and fpDNA and 8. 42% between fpDNA and fuDNA. Patients receiving Hormones also exhibited MIS. Interestingly, fpDNA levels increased significantly in patients with measurable disease who responded to therapy (47.4 ± 13.34 vs 14.37± 5.32; p = 0.021). In vitro, incubating MCF-7 cells and normal PBMNF cells with M ±A, we observed that we could induce MIS in both MCF-7 cells and normal PBMNF cells but A prevented MIS only in normal PBMNF cells. In normal PBMNF cells without A that sustained MIS there was a significantly decreased percentage of cells expressing hMSH2 ( 96% vs 57% p < 0.001). Conclusions: We conclude that Chemotherapy as well as Fulvestran can induce MIS in normal and malignant cells and that in vitro these effects could be reproduced by treatment with M and prevented in normal cells by A. No significant financial relationships to disclose.

Circulating Tumor DNA Alterations in Advanced Urothelial Carcinoma and Association with Clinical Outcomes: A Pilot Study

2020 ◽  
Vol 3 (5) ◽  
pp. 695-699 ◽  
Author(s):  
Petros Grivas ◽  
Aly-Khan A. Lalani ◽  
Gregory R. Pond ◽  
Rebecca J. Nagy ◽  
Bishoy Faltas ◽  
...  
Keyword(s):  
Pilot Study ◽  
Urothelial Carcinoma ◽  
Clinical Outcomes ◽  
Circulating Tumor Dna ◽  
Dna Alterations ◽  
Advanced Urothelial Carcinoma ◽  
Tumor Dna

scholarly journals Circulating tumor DNA alterations in patients with metastatic castration‐resistant prostate cancer

Cancer ◽  
2019 ◽  
Vol 125 (9) ◽  
pp. 1459-1469 ◽  
Author(s):  
Guru Sonpavde ◽  
Neeraj Agarwal ◽  
Gregory Russell Pond ◽  
Rebecca J. Nagy ◽  
Roberto H. Nussenzveig ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Circulating Tumor Dna ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Dna Alterations ◽  
Tumor Dna
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