scholarly journals Assessment of Circulating Copy Number Variant Detection for Cancer Screening

2016 ◽  
Author(s):  
Bhuvan Molparia ◽  
Eshaan Nichani ◽  
Ali Torkamani
Keyword(s):  
Cancer Screening ◽  
Copy Number ◽  
Early Stage ◽  
Point Mutations ◽  
Health Benefit ◽  
High Sensitivity ◽  
Copy Number Variant ◽  
Circulating Tumor Dna ◽  
Detection Methods ◽  
Screening Methods

ABSTRACTCurrent high-sensitivity cancer screening methods suffer from false positive rates that lead to numerous unnecessary procedures and questionable public health benefit overall. Detection of circulating tumor DNA (ctDNA) has the potential to transform cancer screening. Thus far, nearly all ctDNA studies have focused on detection of tumor-specific point mutations. However, ctDNA point mutation detection methods developed to date lack either the scope or sensitivity necessary to be useful for cancer screening, due to the extremely low (<1%) ctDNA fraction derived from early stage tumors. We suggest that tumor-derived copy number variant (CNV) detection is theoretically a superior means of ctDNA-based cancer screening for many tumor types, given that, relative to point mutations, each individual tumor CNV contributes a much larger number of ctDNA fragments to the overall pool of circulating DNA. Here we perform an in silico assessment of the potential for ctDNA CNV-based cancer screening across many common cancers.

scholarly journals Assessment of circulating copy number variant detection for cancer screening

PLoS ONE ◽  
2017 ◽  
Vol 12 (7) ◽  
pp. e0180647 ◽  
Author(s):  
Bhuvan Molparia ◽  
Eshaan Nichani ◽  
Ali Torkamani
Keyword(s):  
Cancer Screening ◽  
Copy Number ◽  
Copy Number Variant ◽  
Variant Detection ◽  
Copy Number Variant Detection

scholarly journals MA 11.02 Circulating Tumor DNA in Early Stage NSCLC: High Sensitivity Analysis in Low Burden Disease. LUCID Study Update

2017 ◽  
Vol 12 (11) ◽  
pp. S1843-S1844 ◽  
Author(s):  
A. Ruiz-Valdepenas ◽  
K. Heider ◽  
G. Doughton ◽  
W. Qian ◽  
C. Massie ◽  
...  
Keyword(s):  
Sensitivity Analysis ◽  
Early Stage ◽  
High Sensitivity ◽  
Circulating Tumor Dna ◽  
Early Stage Nsclc ◽  
Tumor Dna

scholarly journals High-throughput sequencing for noninvasive disease detection in hematologic malignancies

Blood ◽  
2017 ◽  
Vol 130 (4) ◽  
pp. 440-452 ◽  
Author(s):  
Florian Scherer ◽  
David M. Kurtz ◽  
Maximilian Diehn ◽  
Ash A. Alizadeh
Keyword(s):  
High Throughput ◽  
High Throughput Sequencing ◽  
Residual Disease ◽  
High Sensitivity ◽  
Hematologic Malignancies ◽  
Circulating Tumor Dna ◽  
Detection Methods ◽  
Disease Detection ◽  
Molecular Testing ◽  
Molecular Features

Abstract Noninvasive monitoring of minimal residual disease (MRD) has led to significant advances in personalized management of patients with hematologic malignancies. Improved therapeutic options and prolonged survival have further increased the need for sensitive tumor assessment that can inform treatment decisions and patient outcomes. At diagnosis or relapse of most hematologic neoplasms, malignant cells are often easily accessible in the blood as circulating tumor cells (CTCs), making them ideal targets to noninvasively profile the molecular features of each patient. In other cancer types, CTCs are generally rare and noninvasive molecular detection relies on circulating tumor DNA (ctDNA) shed from tumor deposits into circulation. The ability to precisely detect and quantify CTCs and ctDNA could minimize invasive procedures and improve prediction of clinical outcomes. Technical advances in MRD detection methods in recent years have led to reduced costs and increased sensitivity, specificity, and applicability. Among currently available tests, high-throughput sequencing (HTS)–based approaches are increasingly attractive for noninvasive molecular testing. HTS-based methods can simultaneously identify multiple genetic markers with high sensitivity and specificity without individual optimization. In this review, we present an overview of techniques used for noninvasive molecular disease detection in selected myeloid and lymphoid neoplasms, with a focus on the current and future role of HTS-based assays.

scholarly journals Analytical and Clinical Validation of an Amplicon-based Next Generation Sequencing Assay for Ultrasensitive Detection of Circulating Tumor DNA

2021 ◽  
Author(s):  
Jonathan Poh ◽  
Kao Chin Ngeow ◽  
Michelle Pek ◽  
Kian-Hin Tan ◽  
Jing Shan Lim ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Copy Number ◽  
Point Mutations ◽  
Circulating Tumor Dna ◽  
Clinical Validation ◽  
Gene Fusions ◽  
Copy Number Alterations ◽  
Next Generation ◽  
Tumor Dna ◽  
Generation Sequencing

Next-generation sequencing of circulating tumor DNA presents a promising approach to cancer diagnostics, complementing conventional tissue-based diagnostic testing by enabling minimally invasive serial testing and broad genomic coverage through a simple blood draw to maximize therapeutic benefit to patients. LiquidHALLMARK® is an amplicon-based next-generation sequencing assay developed for the genomic profiling of plasma-derived cell-free DNA. The comprehensive 80-gene panel profiles point mutations, insertions/deletions, copy number alterations, and gene fusions, and further detects oncogenic viruses (EBV and HBV) and microsatellite instability. Here, the analytical and clinical validation of the assay is reported. Analytical validation using reference genetic materials demonstrated a sensitivity of 99.38% for point mutations and 95.83% for insertions/deletions at 0.1% variant allele frequency (VAF), and a sensitivity of 91.67% for gene fusions at 0.5% VAF, with high specificity even at 0.1% VAF (99.11% per-base). The limit of detection for copy number alterations, EBV, HBV, and microsatellite instability were also empirically determined. Orthogonal comparison of EGFR variant calls made by LiquidHALLMARK and a reference allele-specific PCR method for 355 lung cancer specimens revealed an overall concordance of 93.80%, while external validation with cobas® EGFR Mutation Test v2 for 50 lung cancer specimens demonstrated an overall concordance of 84.00%, with a 100% concordance rate for EGFR variants above 0.4% VAF. Clinical application of LiquidHALLMARK in 1,592 consecutive patients demonstrated a high detection rate (74.8% alteration-positive in cancer samples) and broad actionability (50.0% of cancer samples harboring alterations with biological evidence for actionability). Among ctDNA-positive lung cancers, 72.5% harbored at least one biomarker with a guideline-approved drug indication. These results establish the high sensitivity, specificity, accuracy, and precision of the LiquidHALLMARK assay and supports its clinical application for blood-based genomic testing.

Comprehensive landscape of gene amplifications (amps) in tissue and circulating tumor DNA (ctDNA) in metastatic colorectal cancer (mCRC).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 604-604
Author(s):  
Kanwal Pratap Singh Raghav ◽  
Rona Yaeger ◽  
Jonathan M. Loree ◽  
Arvind Dasari ◽  
Van K. Morris ◽  
...  
Keyword(s):  
Copy Number ◽  
Acquired Resistance ◽  
High Sensitivity ◽  
Circulating Tumor Dna ◽  
Tissue Samples ◽  
Individual Gene ◽  
Therapeutic Implications ◽  
Oncogenic Pathways ◽  
Number Variation ◽  
Tumor Dna

604 Background: Amps, as oncogenic and resistance drivers, have therapeutic implications, but unlike mutations, have been sparsely described in mCRC. Functional account is piecemeal due to vague definitions, limited data on co-occurring alterations and use of primary tissue samples nonrepresentative of tumor heterogeneity. Our aim was to define the amp landscape in mCRC using tissue and ctDNA sequencing. Methods: We performed systematic analyses of copy-number variation in 2 cohorts of mCRC patients (pts) [tissue (TC) (N = 1,134) and ctDNA (BC) (N = 3,218)] who had high sensitivity targeted sequencing with MSK-IMPACT (341-468 genes) or Guardant Health (70-73 genes) panel, respectively. For BC, plasma copy number was adjusted (ApCN) to account for variable tumor DNA shedding using max allele frequency and high amp (HAmp) was defined as > 4 copies (similar to predefined tissue cutoff). Results: 166 (15%) and 405 (13%) pts in TC and BC harbored amp in at least one of 18 genes assessed by both panels (Table). Amp prevalence for individual gene was similar in both cohorts ( r = 0.9; P < .01) with RTK amps ( EGFR, ERBB2, MET, FGFR1/2, PDGFRA) seen in 8% pts. Key RTK amps were enriched in RAS/BRAF wild type (RB WT) compared to mutant (RB MUT) (OR 3.5; P < .01) pts in both cohorts, in contrast to low prevalence RTK and non-RTK amps. Median ApCN was higher for RTKs in RB WT vs MUT cases ( ERBB2: 12 vs 5; P = .02). Using validated EGFRab exposure (EGFRi) ctDNA signature, we found that EGFRi pts had higher prevalence of EGFR, MET, BRAF, KRAS, PIK3CA and FGFR1 amps compared to EGFRab naïve pts. Conclusions: While individually uncommon, amps occur across key oncogenic pathways in mCRC and after adjusting for ctDNA shedding, are seen at similar prevalence in tissue and plasma. Amps in RTKs are seen in 10-12% of RB WT tumors, suggesting clinically relevant roles as oncogenic effectors and targets. After EGFRi, a number of amps emerge, including PIK3CA and FGFR1 amps, not previously implicated in acquired resistance. [Table: see text]

scholarly journals Circulating tumor DNA (ctDNA) as a pan-cancer screening test: is it finally on the horizon?

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Michael J. Duffy ◽  
Eleftherios P. Diamandis ◽  
John Crown
Keyword(s):  
Cancer Screening ◽  
Screening Test ◽  
Early Stage ◽  
Circulating Tumor Dna ◽  
Cancer Type ◽  
Protein Biomarkers ◽  
Cancer Screening Test ◽  
Copy Number Changes ◽  
Pan Cancer ◽  
Tumor Dna

Abstract The detection of cancer at an early stage while it is curable by surgical resection is widely believed to be one of the most effective strategies for reducing cancer mortality. Hence, the intense interests in the development of a simple pan-cancer screening test. Lack of sensitivity and specificity when combined with the low prevalence of most types of cancer types in the general population limit the use of most of the existing protein biomarkers for this purpose. Like proteins, tumor DNA also can be released into the circulation. Such circulating tumor DNA (ctDNA) can be differentiated from normal cell DNA by the presence of specific genetic alteration such as mutations, copy number changes, altered methylation patterns or being present in different sized fragments. Emerging results with test such as CancerSEEK or GRAIL suggest that the use of ctDNA can detect cancer with specificities >99%. Sensitivity however, is cancer type and stage-dependent, varying from approximately 40% in stage I disease to approximately 80% in stage III disease. It is important to stress however, that most of the studies published to date have used patients with an established diagnosis of cancer while the control population were healthy individuals. Although the emerging results are promising, evidence of clinical utility will require demonstration of reduced mortality following evaluation in a prospective randomized screening trial.

Early Detection of Cancer: Past, Present, and Future

2015 ◽  
pp. 57-65 ◽  
Author(s):  
Joshua D. Schiffman ◽  
Paul G. Fisher ◽  
Peter Gibbs
Keyword(s):  
Cancer Screening ◽  
Circulating Tumor Dna ◽  
Screening Tests ◽  
Current Status ◽  
Screening Methods ◽  
Clinical Consequence ◽  
Curative Intent ◽  
High Risk Populations ◽  
Early Tumor ◽  
The Cost

Screening in both healthy and high-risk populations offers the opportunity to detect cancer early and with an increased opportunity for treatment and curative intent. Currently, a defined role for screening exists in some cancer types, but each screening test has limitations, and improved screening methods are urgently needed. Unfortunately, many cancers still lack effective screening recommendations, or in some cases, the benefits from screening are marginal when weighed against the potential for harm. Here we review the current status of cancer screening: we examine the role of traditional tumor biomarkers, describe recommended imaging for early tumor surveillance, and explore the potential of promising novel cancer markers such as circulating tumor cells (CTC) and circulating tumor DNA. Consistent challenges for all of these screening tests include limited sensitivity and specificity. The risk for overdiagnosis remains a particular concern in screening, whereby lesions of no clinical consequence may be detected and thus create difficult management decisions for the clinician and patient. If treatment is pursued following overdiagnosis, patients may be exposed to morbidity from a treatment that may not provide any true benefit. The cost-effectiveness of screening tests also needs to be an ongoing focus. The improvement of genomic and surveillance technologies, which leads to more precise imaging and the ability to characterize blood-based tumor markers of greater specificity, offers opportunities for major progress in cancer screening.

scholarly journals Novel DNA methylation biomarkers show high sensitivity and specificity for blood-based detection of colorectal cancer—a clinical biomarker discovery and validation study

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Sarah Østrup Jensen ◽  
Nadia Øgaard ◽  
Mai-Britt Worm Ørntoft ◽  
Mads Heilskov Rasmussen ◽  
Jesper Bertram Bramsen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Methylation ◽  
Sensitivity And Specificity ◽  
Biomarker Discovery ◽  
Early Stage ◽  
Stage Iv ◽  
High Sensitivity ◽  
Digital Pcr ◽  
Minimal Invasive ◽  
Screening Methods

Abstract Background Early detection plays an essential role to reduce colorectal cancer (CRC) mortality. While current screening methods suffer from poor compliance, liquid biopsy-based strategies for cancer detection is rapidly gaining promise. Here, we describe the development of TriMeth, a minimal-invasive blood-based test for detection of early-stage colorectal cancer. The test is based on assessment of three tumour-specific DNA methylation markers in circulating cell-free DNA. Results A thorough multi-step biomarker discovery study based on DNA methylation profiles of more than 5000 tumours and blood cell populations identified CRC-specific DNA methylation markers. The DNA methylation patterns of biomarker candidates were validated by bisulfite sequencing and methylation-specific droplet digital PCR in CRC tumour tissue and peripheral blood leucocytes. The three best performing markers were first applied to plasma from 113 primarily early-stage CRC patients and 87 age- and gender-matched colonoscopy-verified controls. Based on this, the test scoring algorithm was locked, and then TriMeth was validated in an independent cohort comprising 143 CRC patients and 91 controls. Three DNA methylation markers, C9orf50, KCNQ5, and CLIP4, were identified, each capable of discriminating plasma from colorectal cancer patients and healthy individuals (areas under the curve 0.86, 0.91, and 0.88). When combined in the TriMeth test, an average sensitivity of 85% (218/256) was observed (stage I: 80% (33/41), stage II: 85% (121/143), stage III: 89% (49/55), and stage IV: 88% (15/17)) at 99% (176/178) specificity in two independent plasma cohorts. Conclusion TriMeth enables detection of early-stage colorectal cancer with high sensitivity and specificity. The reported results underline the potential utility of DNA methylation-based detection of circulating tumour DNA in the clinical management of colorectal cancer.

A CLINICAL CASE OF PRIMARY HYPERPARATHYROIDISM OF THE OSTEO-VISCERAL FORM

2020 ◽  
pp. 155-161
Author(s):  
Poselyugina O.B. ◽  
Kulish A.S. ◽  
Vasiliev D.F.
Keyword(s):  
Primary Hyperparathyroidism ◽  
Clinical Case ◽  
Early Stage ◽  
Diagnostic Errors ◽  
Epidemiological Studies ◽  
Medical Documentation ◽  
Screening Methods ◽  
Internal Organs ◽  
Blood Calcium ◽  
Slow Development

Introduction. Primary hyperparathyroidism is an endocrine disease resulting from a primary pathology of the parathyroid gland, characterized by increased secretion of parathyroid hormone and increased blood calcium levels. Among the endocrine diseases, primary hyperparathyroidism is the third most common after diabetes mellitus and thyroid disease. In Russia, according to epidemiological studies, primary hyperparathyroidism is found in 1% of the population, women suffer 2-3 times more often than men do, and the average age of diagnosis is 54-59 years. In the absence of a timely diagnosis, primary hyperparathyroidism causes systemic damage to internal organs: renal impairment, nephrolithiasis, esophageal affection, cardiovascular and nervous system involvement, and it leads to a violation of bone tissue integrity. The aim is to demonstrate a clinical case of a patient with primary hyperparathyroidism and to analyze the stages of diagnosis of the disease and treatment. Material and methods. The review of medical literature on the problem of diagnostics and treatment of primary hyperparathyroidism was performed, as well as an analysis of the patient’s medical documentation with this pathology. Results and discussion. A variant of complicated course of primary hyperparathyroidism of bone and visceral form is considered. About 15 years passed from the moment of appearance of the first symptoms of the disease to the development of complications of renal and bone system. Despite the slow development of the disease and availability of screening methods, hyperparathyroidism was detected at the stage of complications. This article provides a detailed analysis of the primary hyperparathyroidism history, as well as analyzes the possibilities of diagnosis, treatment and prevention of this pathology. The efficacy of the therapy has been assessed, and ways of correction have been outlined. The analysis of the reasons that made it difficult to diagnose this pathology at an early stage, before the development of serious complications of internal organs, has been carried out. Conclusions: It can be assumed that the presented clinical case will increase the awareness of physicians, especially therapists, about the primary manifestations of this pathology and the peculiarities of its detection and routing the patient, which will allow avoiding many diagnostic errors.

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