Noninvasive molecular profiling of high-risk relapsed neuroblastoma by plasma cell-free DNA analysis.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 10552-10552
Author(s):  
Prachi Kothari ◽  
Julie Yang ◽  
Michael F. Berger ◽  
Neerav Narendra Shukla ◽  
Shakeel Modak ◽  
...  
Keyword(s):  
High Risk ◽  
Disease Progression ◽  
Dna Analysis ◽  
Matched Control ◽  
Multimodality Treatment ◽  
Molecular Profiling ◽  
Mycn Amplification ◽  
Cell Free Dna ◽  
Free Dna ◽  
Control Samples

10552 Background: Neuroblastoma (NB) is the most common extracranial solid tumor in children. 5-year survival rates for high-risk NB are < 50% despite intense multimodality treatment. Recent studies revealed that as opposed to diagnostic samples, relapsed NB tumors have a significantly higher mutational burden as a result of clonal evolution. This poses a challenge for the development of personalized therapies and warrants molecular profiling at relapse. However, tumor samples are not always accessible at relapse. Our study evaluates the feasibility of using cell-free DNA (cfDNA) to noninvasively characterize tumor profiles at relapse to identify targetable genetic variants. Methods: Tumor specimens, plasma and matched control samples from 10 patients with high-risk stage 4 NB were collected during multimodality treatment. Samples were analyzed using the MSK-IMPACT platform, a targeted deep sequencing assay to interrogate the exons and selected introns of 410 actionable genes. Tumor samples were collected from surgeries performed either at diagnosis, disease progression, or relapse. Plasma samples were collected at a time of disease progression, at an average 395 days (range of 47-1597 days) from tumor collection. Matched control samples were used to filter germline variants. Results: We detected somatic mutations and copy number alterations in tumor tissues and cfDNA of 10/10 and 6/10 patients, respectively. These included recurrent NB drivers such as MYCN amplification and ATRX mutations. In 4 patients, cfDNA also revealed somatic variants that were not detected in the original tumor specimens, including potentially targetable mutations in NRAS, MLL2, CIC and IDH2 that were recently reported to be enriched in the relapse setting, as well as ARID1B mutation that is associated with poor prognosis. Conclusions: This study suggests that it is feasible to noninvasively profile the dynamic genetic heterogeneity of NB by plasma cfDNA analysis. Such analysis can potentially supplement tumor profiling especially in the relapse setting to guide treatment plans. Our findings call for incorporation of cfDNA analysis in clinical trials to further evaluate its utility for clinical management of NB patients.

Plasma cell-free DNA for noninvasive molecular profiling in high-risk stage 4 neuroblastoma.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. 10554-10554 ◽  
Author(s):  
Prachi Kothari ◽  
Julie Yang ◽  
Michael F. Berger ◽  
Neerav Narendra Shukla ◽  
Shakeel Modak ◽  
...  
Keyword(s):  
High Risk ◽  
Plasma Cell ◽  
Molecular Profiling ◽  
Cell Free Dna ◽  
Free Dna ◽  
Stage 4

A dual target sequencing solution to assess genomic and epigenomic alterations in cell-free DNA with no sample splitting.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3043-3043
Author(s):  
Grace Q. Zhao ◽  
Yun Bao ◽  
Heng Wang ◽  
Wanping Hu ◽  
John Coller ◽  
...  
Keyword(s):  
Cancer Detection ◽  
Dna Analysis ◽  
Residual Disease ◽  
Early Stage ◽  
Cancer Cell Line ◽  
Assay Sensitivity ◽  
Cell Free Dna ◽  
Target Sequencing ◽  
Free Dna ◽  
Dual Analysis

3043 Background: Assessing the genomic and epigenomic changes on plasma cell-free DNA (cfDNA) using next-generation sequencing (NGS) has become increasingly important for cancer detection and treatment selection guidance. However, two major hurdles of existing targeted NGS methods make them impractical for the clinical setting. First, there is no comprehensive, end to end, kit solution available for targeted methylation sequencing (TMS), let alone one that analyzes both mutation and methylation information in one assay. Second, the low yield of cfDNA from clinical blood samples presents a major challenge for conducting multi-omic analysis. Thus, an assay that is capable of both genomic and epigenomic analysis would be advantageous for clinical research and future diagnostic assays. Methods: Here, we report the performance of Point-n-SeqTM dual analysis, a kit solution that can provide in-depth DNA analysis with highly flexible and customizable focused panels to enable both genomic and epigenomic analysis without sample splitting. With custom panels of tens to thousands of markers designed with > 99% first-pass success rate, we conducted both performance validation and multi-center, multi-operator, reproducibility studies. Using spike-in titration of cancer cell-line gDNA with known mutation and methylation profiles, Point-n-Seq assay achieved a reliable detection level down to 0.003% of tumor DNA with a linear relationship between the measured and expected fractions. Benchmarked with conventional targeted sequencing and methylation sequencing, Point-n-Seq solution also demonstrated improved performance, speed and shortened hands-on time. Results: In a pilot clinical study, a colorectal cancer (CRC) TMS panel covering 560 methylation markers and a mutation panel with > 350 hotspot mutations in 22 genes were used in the dual assay. Using 1ml of plasma from late-stage CRC patients, cancer-specific methylation signals were detected in all samples tested, and oncogenic mutations. In an early-stage cohort (33 stage I/II CRC patient ), comparison of the analysis between tumor-informed, personalized-mutation panels (̃100 private SNVs) for each patient and the tumor-independent CRC methylation panels were conducted. The initial results showed that tumor-independent TMS assay achieved a comparable detection compared to the personalized tumor-informed approach. Moreover, cfDNA size information (fragmentome) is also integrated into the analysis of the same Point-n-Seq workflow to improve the assay sensitivity. Conclusions: Point-n-Seq dual analysis is poised to advance both research and clinical applications of early cancer detection, minimal residual disease (MRD), and monitoring.

Cell-Free DNA Analysis in Maternal Blood: Differences in Estimates between Laboratories with Different Methodologies Using a Propensity Score Approach

2018 ◽  
Vol 45 (5) ◽  
pp. 302-311 ◽  
Author(s):  
Elisa Bevilacqua ◽  
Jacques C. Jani ◽  
Alexandra Letourneau ◽  
Silvia F. Duiella ◽  
Pascale Kleinfinger ◽  
...  
Keyword(s):  
Propensity Score ◽  
Dna Analysis ◽  
Maternal Blood ◽  
Cell Free Dna ◽  
Free Dna

Cell-Free DNA Screening for Fetal Aneuploidy

2021 ◽  
pp. 115-120
Author(s):  
Ashley N. Battarbee ◽  
Neeta L. Vora
Keyword(s):  
Trisomy 21 ◽  
Dna Analysis ◽  
Chromosomal Abnormalities ◽  
Area Under The Curve ◽  
First Trimester ◽  
Outcome Data ◽  
Cell Free Dna ◽  
High Risk Women ◽  
Free Dna ◽  
Trimester Screening

In a prospective, multicenter blinded study at 35 international centers, the Noninvasive Examination of Trisomy (NEXT) study evaluated the performance of cell-free DNA screening for fetal trisomy compared to standard first trimester screening with nuchal translucency and serum analytes in a routine prenatal population. Among the 15,841 women who had standard screening and cell-free DNA analysis with neonatal outcome data, there were 68 chromosomal abnormalities (1 in 236). Of these, 38 were Trisomy 21 (1 in 417). Cell-free DNA analysis had a higher area under the curve (AUC) for trisomy 21, compared to standard screening (0.999 vs. 0.958, p = 0.001). Cell-free DNA analysis also had greater sensitivity, specificity, and positive predictive value compared to standard screening for trisomy 21, 18, and 13. While cell-free DNA analysis cannot detect all chromosome abnormalities, it performed better than standard screening for detection of trisomies 21, 18, and 13 in a routine population including low- and high-risk women.

scholarly journals Implementation of cell-free DNA-based non-invasive prenatal testing in a National Health Service Regional Genetics Laboratory

2019 ◽  
Vol 101 ◽  
Author(s):  
Fiona S. Togneri ◽  
Mark D. Kilby ◽  
Elizabeth Young ◽  
Samantha Court ◽  
Denise Williams ◽  
...  
Keyword(s):  
National Health Service ◽  
High Risk ◽  
Health Service ◽  
National Health ◽  
Prenatal Testing ◽  
Low Risk ◽  
Trisomy 13 ◽  
Cell Free Dna ◽  
Non Invasive ◽  
Free Dna

Abstract Background Non-invasive prenatal testing (NIPT) for the detection of foetal aneuploidy through analysis of cell-free DNA (cfDNA) in maternal blood is offered routinely by many healthcare providers across the developed world. This testing has recently been recommended for evaluative implementation in the UK National Health Service (NHS) foetal anomaly screening pathway as a contingent screen following an increased risk of trisomy 21, 18 or 13. In preparation for delivering a national service, we have implemented cfDNA-based NIPT in our Regional Genetics Laboratory. Here, we describe our validation and verification processes and initial experiences of the technology prior to rollout of a national screening service. Methods Data are presented from more than 1000 patients (215 retrospective and 840 prospective) from ‘high- and low-risk pregnancies’ with outcome data following birth or confirmatory invasive prenatal sampling. NIPT was by the Illumina Verifi® test. Results Our data confirm a high-fidelity service with a failure rate of ~0.24% and a high sensitivity and specificity for the detection of foetal trisomy 13, 18 and 21. Secondly, the data show that a significant proportion of patients continue their pregnancies without prenatal invasive testing or intervention after receiving a high-risk cfDNA-based result. A total of 46.5% of patients referred to date were referred for reasons other than high screen risk. Ten percent (76/840 clinical service referrals) of patients were referred with ultrasonographic finding of a foetal structural anomaly, and data analysis indicates high- and low-risk scan indications for NIPT. Conclusions NIPT can be successfully implemented into NHS regional genetics laboratories to provide high-quality services. NHS provision of NIPT in patients with high-risk screen results will allow for a reduction of invasive testing and partially improve equality of access to cfDNA-based NIPT in the pregnant population. Patients at low risk for a classic trisomy or with other clinical indications are likely to continue to access cfDNA-based NIPT as a private test.

scholarly journals Clinical Utility of Comprehensive Cell-free DNA Analysis to Identify Genomic Biomarkers in Patients with Newly Diagnosed Metastatic Non–small Cell Lung Cancer

2019 ◽  
Vol 25 (15) ◽  
pp. 4691-4700 ◽  
Author(s):  
Natasha B. Leighl ◽  
Ray D. Page ◽  
Victoria M. Raymond ◽  
Davey B. Daniel ◽  
Stephen G. Divers ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Clinical Utility ◽  
Dna Analysis ◽  
Small Cell ◽  
Newly Diagnosed ◽  
Small Cell Lung ◽  
Cell Free Dna ◽  
Free Dna
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