scholarly journals Genome-wide cell-free DNA screening: a focus on copy-number variants

2021 ◽  
Author(s):  
Jill Rafalko ◽  
Erica Soster ◽  
Samantha Caldwell ◽  
Eyad Almasri ◽  
Thomas Westover ◽  
...  
Keyword(s):  
Copy Number ◽  
Chromosomal Abnormalities ◽  
Diagnostic Testing ◽  
Copy Number Variants ◽  
Cell Free Dna ◽  
Predictive Values ◽  
Free Dna ◽  
Genome Wide ◽  
Cfdna Screening ◽  
Diagnostic Outcomes

Abstract Purpose Of 86,902 prenatal genome-wide cell-free DNA (cfDNA) screening tests, 4,121 were positive for a chromosome abnormality. This study examines 490 cases screen-positive for one or more subchromosomal copy-number variants (CNV) from genome-wide cfDNA screening. Methods Cases positive for one or more subchromosomal CNV from genome-wide cfDNA screening and diagnostic outcomes were compiled. Diagnostic testing trends were analyzed, positive predictive values (PPVs) were calculated, and the type of chromosomal abnormalities ultimately confirmed by diagnostic testing were described. Results CNVs were identified in 0.56% of screened specimens. Of the 490 cases screen-positive for one or more CNV, diagnostic outcomes were available for 244 cases (50%). The overall PPV among the cases with diagnostic outcomes was 74.2% (95% CI: 68.1–79.5%) and 71.8% (95% CI: 65.5–77.4%) for “fetal-only” events. Overall, isolated CNVs showed a lower PPV of 61.0% (95% CI: 52.5–68.8%) compared to complex CNVs at 93.9% (95% CI: 86.6–97.5%). Isolated deletions/duplications and unbalanced structural rearrangements were the most common diagnostic outcomes when isolated and complex CNVs were identified by cfDNA screening, respectively. Conclusion Genome-wide cfDNA screening identifies chromosomal abnormalities beyond the scope of traditional cfDNA screening, and the overall PPV associated with subchromosomal CNVs in cases with diagnostic outcomes was >70%.

scholarly journals Three years of clinical experience with a genome-wide cfDNA screening test for aneuploidies and copy-number variants

2021 ◽  
Author(s):  
Erica Soster ◽  
Theresa Boomer ◽  
Susan Hicks ◽  
Samantha Caldwell ◽  
Brittany Dyr ◽  
...  
Keyword(s):  
Test Performance ◽  
Copy Number ◽  
Clinical Performance ◽  
Diagnostic Testing ◽  
Copy Number Variants ◽  
High Sensitivity ◽  
Clinical Population ◽  
Genome Wide ◽  
A Genome ◽  
Cfdna Screening

Abstract Purpose Pregnant women have unprecedented choices for prenatal screening and testing. Cell-free DNA (cfDNA) offers the option to screen for aneuploidy of all chromosomes and genome-wide copy-number variants (CNVs), expanding screening beyond the common trisomies (“traditional” cfDNA). We sought to review the utilization trends and clinical performance characteristics of a commercially available genome-wide cfDNA test, with a subset having available diagnostic testing outcomes. Methods Retrospective analysis of 55,517 samples submitted for genome-wide cfDNA screening at a commercial laboratory, assessing indications, demographics, results, and performance. The cohort was broken into three “testing years”’ to compare trends. Results Indications shifted over time, with a decrease in referrals for ultrasound findings (22.0% to 12.0%) and an increase in no known high-risk indication (3.0% to 16.6%). Of the positive results, 25% would be missed with traditional cfDNA screening. High sensitivity and specificity were observed with a positive predictive value (PPV) of 72.6% for genome-wide CNVs and 22.4% for rare autosomal trisomies (RATs). Conclusion A broader patient population is utilizing genome-wide cfDNA, yet positivity rates and the contribution of genome-wide events have remained stable at approximately 5% and 25%, respectively. Test performance in a real-world clinical population shows high PPVs in those CNVs tested, with diagnostic outcomes in over 40% of positive cases.

scholarly journals False positive cell free DNA screening for microdeletions due to non-pathogenic copy number variants

2016 ◽  
Vol 36 (6) ◽  
pp. 584-586 ◽  
Author(s):  
Cheryl A. Mather ◽  
Zhongxia Qi ◽  
Arun P. Wiita
Keyword(s):  
False Positive ◽  
Copy Number ◽  
Copy Number Variants ◽  
Cell Free Dna ◽  
Free Dna

scholarly journals Detection of Clonal and Subclonal Copy-Number Variants in Cell-Free DNA from Patients with Breast Cancer Using a Massively Multiplexed PCR Methodology

2015 ◽  
Vol 8 (5) ◽  
pp. 407-416 ◽  
Author(s):  
Eser Kirkizlar ◽  
Bernhard Zimmermann ◽  
Tudor Constantin ◽  
Ryan Swenerton ◽  
Bin Hoang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Copy Number ◽  
Copy Number Variants ◽  
Cell Free Dna ◽  
Multiplexed Pcr ◽  
Free Dna

Genome-wide detection of additional fetal chromosomal abnormalities by cell-free DNA testing of 15,626 consecutive pregnant women

2018 ◽  
Vol 62 (2) ◽  
pp. 215-224 ◽  
Author(s):  
Hong Yao ◽  
Ya Gao ◽  
Jia Zhao ◽  
Rong Zhang ◽  
Huixin Xu ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Chromosomal Abnormalities ◽  
Dna Testing ◽  
Cell Free Dna ◽  
Free Dna ◽  
Genome Wide

scholarly journals Cell-Free-DNA-Based Copy Number Index Score in Epithelial Ovarian Cancer—Impact for Diagnosis and Treatment Monitoring

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 168
Author(s):  
Elena Ioana Braicu ◽  
Andreas du Bois ◽  
Jalid Sehouli ◽  
Julia Beck ◽  
Sonia Prader ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Copy Number ◽  
High Grade ◽  
Copy Number State ◽  
Cell Free Dna ◽  
Blood Samples ◽  
Free Dna ◽  
Genome Wide ◽  
A Genome

Background: Chromosomal instability, a hallmark of cancer, results in changes in the copy number state. These deviant copy number states can be detected in the cell-free DNA (cfDNA) and provide a quantitative measure of the ctDNA levels by converting cfDNA next-generation sequencing results into a genome-wide copy number instability score (CNI-Score). Our aim was to determine the role of the CNI-Score in detecting epithelial ovarian cancer (EOC) and its role as a marker to monitor the response to treatment. Methods: Blood samples were prospectively collected from 109 patients with high-grade EOC. cfDNA was extracted and analyzed using a clinical-grade assay designed to calculate a genome-wide CNI-Score from low-coverage sequencing data. Stored data from 241 apparently healthy controls were used as a reference set. Results: Comparison of the CNI-Scores of primary EOC patients versus controls yielded sensitivities of 91% at a specificity of 95% to detect OC, respectively. Significantly elevated CNI-Scores were detected in primary (median: 87, IQR: 351) and recurrent (median: 346, IQR: 1891) blood samples. Substantially reduced CNI-Scores were detected after primary debulking surgery. Using a cut-off of 24, a diagnostic sensitivity of 87% for primary and recurrent EOC was determined at a specificity of 95%. CNI-Scores above this threshold were detected in 21/23 primary tumor (91%), 36/42 of platinum-eligible recurrent (85.7%), and 19/22 of non-platinum-eligible recurrent (86.3%) samples, respectively. Conclusion: ctDNA-quantification based on genomic instability determined by the CNI-Score was a biomarker with high diagnostic accuracy in high-grade EOC. The applied assay might be a promising tool for diagnostics and therapy monitoring, as it requires no a priori information about the tumor.

scholarly journals Association of Cell-Free DNA Tumor Fraction and Somatic Copy Number Alterations With Survival in Metastatic Triple-Negative Breast Cancer

2018 ◽  
Vol 36 (6) ◽  
pp. 543-553 ◽  
Author(s):  
Daniel G. Stover ◽  
Heather A. Parsons ◽  
Gavin Ha ◽  
Samuel S. Freeman ◽  
William T. Barry ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Copy Number ◽  
Triple Negative ◽  
Copy Number Alterations ◽  
Cell Free Dna ◽  
Primary Tumors ◽  
Free Dna ◽  
Genome Wide ◽  
Somatic Copy Number Alterations

Purpose Cell-free DNA (cfDNA) offers the potential for minimally invasive genome-wide profiling of tumor alterations without tumor biopsy and may be associated with patient prognosis. Triple-negative breast cancer (TNBC) is characterized by few mutations but extensive somatic copy number alterations (SCNAs), yet little is known regarding SCNAs in metastatic TNBC. We sought to evaluate SCNAs in metastatic TNBC exclusively via cfDNA and determine if cfDNA tumor fraction is associated with overall survival in metastatic TNBC. Patients and Methods In this retrospective cohort study, we identified 164 patients with biopsy-proven metastatic TNBC at a single tertiary care institution who received prior chemotherapy in the (neo)adjuvant or metastatic setting. We performed low-coverage genome-wide sequencing of cfDNA from plasma. Results Without prior knowledge of tumor mutations, we determined tumor fraction of cfDNA for 96.3% of patients and SCNAs for 63.9% of patients. Copy number profiles and percent genome altered were remarkably similar between metastatic and primary TNBCs. Certain SCNAs were more frequent in metastatic TNBCs relative to paired primary tumors and primary TNBCs in publicly available data sets The Cancer Genome Atlas and METABRIC, including chromosomal gains in drivers NOTCH2, AKT2, and AKT3. Prespecified cfDNA tumor fraction threshold of ≥ 10% was associated with significantly worse metastatic survival (median, 6.4 v 15.9 months) and remained significant independent of clinicopathologic factors (hazard ratio, 2.14; 95% CI, 1.4 to 3.8; P < .001). Conclusion We present the largest genomic characterization of metastatic TNBC to our knowledge, exclusively from cfDNA. Evaluation of cfDNA tumor fraction was feasible for nearly all patients, and tumor fraction ≥ 10% is associated with significantly worse survival in this large metastatic TNBC cohort. Specific SCNAs are enriched and prognostic in metastatic TNBC, with implications for metastasis, resistance, and novel therapeutic approaches.

Sign in / Sign up

Export Citation Format

Share Document