scholarly journals Enhanced specificity of clinical high-sensitivity tumor mutation profiling in cell-free DNA via paired normal sequencing using MSK-ACCESS

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
A. Rose Brannon ◽  
Gowtham Jayakumaran ◽  
Monica Diosdado ◽  
Juber Patel ◽  
Anna Razumova ◽  
...  
Keyword(s):  
Cancer Patients ◽  
De Novo ◽  
Low Frequency ◽  
High Sensitivity ◽  
Clinical Analysis ◽  
De Novo Mutation ◽  
Cell Free Dna ◽  
Free Dna ◽  
Somatic Alterations ◽  
Mutation Profiling

AbstractCirculating cell-free DNA from blood plasma of cancer patients can be used to non-invasively interrogate somatic tumor alterations. Here we develop MSK-ACCESS (Memorial Sloan Kettering - Analysis of Circulating cfDNA to Examine Somatic Status), an NGS assay for detection of very low frequency somatic alterations in 129 genes. Analytical validation demonstrated 92% sensitivity in de-novo mutation calling down to 0.5% allele frequency and 99% for a priori mutation profiling. To evaluate the performance of MSK-ACCESS, we report results from 681 prospective blood samples that underwent clinical analysis to guide patient management. Somatic alterations are detected in 73% of the samples, 56% of which have clinically actionable alterations. The utilization of matched normal sequencing allows retention of somatic alterations while removing over 10,000 germline and clonal hematopoiesis variants. Our experience illustrates the importance of analyzing matched normal samples when interpreting cfDNA results and highlights the importance of cfDNA as a genomic profiling source for cancer patients.

scholarly journals Enhanced specificity of high sensitivity somatic variant profiling in cell-free DNA via paired normal sequencing: design, validation, and clinical experience of the MSK-ACCESS liquid biopsy assay

2020 ◽  
Author(s):  
A. Rose Brannon ◽  
Gowtham Jayakumaran ◽  
Monica Diosdado ◽  
Juber Patel ◽  
Anna Razumova ◽  
...  
Keyword(s):  
De Novo ◽  
Low Frequency ◽  
Treatment Resistance ◽  
High Sensitivity ◽  
Clinical Analysis ◽  
De Novo Mutation ◽  
Normal Sample ◽  
Cell Free Dna ◽  
Free Dna ◽  
Somatic Alterations

AbstractCirculating cell-free DNA (cfDNA) from blood plasma of cancer patients can be used to interrogate somatic tumor alterations non-invasively or when adequate tissue is unavailable. We have developed and clinically implemented MSK-ACCESS (Analysis of Circulating cfDNA to Evaluate Somatic Status), an NGS assay for detection of very low frequency somatic alterations in select exons and introns of 129 genes. Analytical validation demonstrated 92% sensitivity in de-novo mutation calling down to 0.5% allele frequency and 98% for a priori mutation profiling. To evaluate the performance and utility of MSK-ACCESS, we report results from the first 681 prospective blood samples (617 patients) that underwent clinical analysis to guide patient management. Somatic mutations, copy number, and/or structural variants were detected in 73% of the samples, and 56% of these circulating-tumor DNA (ctDNA) positive samples had clinically actionable alterations. The utilization of matched white blood cell sequencing allowed retention of somatic alterations while filtering out over 10,000 germline and clonal hematopoiesis variants, thereby greatly enhancing the specificity of the assay. Taken together, our experience illustrates the importance of analyzing a matched normal sample when interpreting cfDNA results and highlights the potential of cfDNA profiling to guide treatment selection, monitor treatment response, and identify mechanisms of treatment resistance.

scholarly journals Enhanced specificity of high sensitivity somatic variant profiling in cell-free DNA via paired normal sequencing: design, validation, and clinical experience of the MSK-ACCESS liquid biopsy assay

2020 ◽  
Author(s):  
Angela Rose Brannon ◽  
Gowtham Jayakumaran ◽  
Monica Diosdado ◽  
Juber Patel ◽  
Anna Razumova ◽  
...  
Keyword(s):  
De Novo ◽  
Low Frequency ◽  
Treatment Resistance ◽  
High Sensitivity ◽  
Clinical Analysis ◽  
De Novo Mutation ◽  
Normal Sample ◽  
Cell Free Dna ◽  
Free Dna ◽  
Somatic Alterations

Abstract Circulating cell-free DNA (cfDNA) from blood plasma of cancer patients can be used to interrogate somatic tumor alterations non-invasively or when adequate tissue is unavailable. We have developed and clinically implemented MSK-ACCESS (Analysis of Circulating cfDNA to Evaluate Somatic Status), an NGS assay for detection of very low frequency somatic alterations in select exons and introns of 129 genes. Analytical validation demonstrated 92% sensitivity in de-novo mutation calling down to 0.5% allele frequency and 99% for a priori mutation profiling. To evaluate the performance and utility of MSK-ACCESS, we report results from the first 681 prospective blood samples (617 patients) that underwent clinical analysis to guide patient management. Somatic mutations, copy number, and/or structural variants were detected in 73% of the samples, and 56% of these circulating-tumor DNA (ctDNA) positive samples had clinically actionable alterations. The utilization of matched white blood cell sequencing allowed retention of somatic alterations while filtering out over 10,000 germline and clonal hematopoiesis variants, thereby greatly enhancing the specificity of the assay. Taken together, our experience illustrates the importance of analyzing a matched normal sample when interpreting cfDNA results and highlights the potential of cfDNA profiling to guide treatment selection, monitor treatment response, and identify mechanisms of treatment resistance.

scholarly journals Clonal Hematopoiesis in Lung Cancer and Its Impact on Liquid Biopsy Based on Targeted Deep Sequencing

2021 ◽  
Author(s):  
Yang Xue ◽  
Youyu Wang ◽  
Yingmei Li ◽  
Danni Liu ◽  
Mengqi Shao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Liquid Biopsy ◽  
Detection Rate ◽  
Low Frequency ◽  
Cell Free Dna ◽  
High Background ◽  
Lung Cancer Patients ◽  
Clonal Hematopoiesis ◽  
Free Dna

Abstract Background: Blood based liquid biopsy has proved its potential in enormous clinical applications, such as cancer screening, diagnosis, treatment guidance, disease tracking and monitoring. In certain scenario (e.g., molecular residual disease), it requires the technique to be able to detect mutation with very low frequency (0.001% ~ 1%). The major hurdle of ultra-sensitive circulating tumor DNA sequencing is the high background noise of plasma cell-free DNA (cfDNA) and clonal hematopoiesis (CH). Here in this study, we investigated the prevalence of CH in lung cancer patients and its interference with liquid biopsy. Methods: We retrospectively analyzed cfDNA and blood cell genomic DNA (gDNA) sequencing data sets (n=1261) from a group of Chinese lung cancer patients. Threshold (1%) and subthreshold (0.2%) for variant allele frequency were set and compared. We focused on 23 clonal hematopoiesis genes that were selected based on previous publications. Results: CH mutations were detected in 27.68% of all the patients at the threshold and 62.01% at the subthreshold, and the detection rate increased with age. DNMT3A was the most frequently mutated CH gene, accounted for more than half of the CH mutations. The CH mutations had a higher detection rate in smokers (72%) than non-smokers (59.4%) at subthreshold. VAFs of CH mutations in cell-free DNA strongly correlated with their VAFs in gDNA (Pearson’s R =0.92, p<2.2x10-16), while tumor derived somatic mutations didn’t have such correlation. Conclusion: Our study showed that clonal hematopoiesis is very common in lung cancer patients, especially when examining low frequency mutations. Sequencing of gDNA at equivalent depth is very important to filter out CH mutation in cancer liquid biopsy.

Potential clinical applications of circulating cell-free DNA in ovarian cancer patients

2018 ◽  
Vol 20 ◽  
Author(s):  
Ana Barbosa ◽  
Ana Peixoto ◽  
Pedro Pinto ◽  
Manuela Pinheiro ◽  
Manuel R. Teixeira
Keyword(s):  
Ovarian Cancer ◽  
Cancer Patients ◽  
Liquid Biopsy ◽  
Clinical Applications ◽  
Epigenetic Alterations ◽  
Cell Free Dna ◽  
Non Invasive ◽  
Free Dna ◽  
Potential Use ◽  
Circulating Cell Free Dna

AbstractCirculating cell-free DNA (cfDNA) consists of small fragments of DNA that circulate freely in the bloodstream. In cancer patients, a fraction of cfDNA is derived from tumour cells, therefore containing the same genetic and epigenetic alterations, and is termed circulating cell-free tumour DNA. The potential use of cfDNA, the so-called ‘liquid biopsy’, as a non-invasive cancer biomarker has recently received a lot of attention. The present review will focus on studies concerning the potential clinical applications of cfDNA in ovarian cancer patients.

Circulating cell-free DNA in plasma of colorectal cancer patients - A potential biomarker for tumor burden

2017 ◽  
Vol 26 (4) ◽  
pp. 395-401 ◽  
Author(s):  
Jagdeep Singh Bhangu ◽  
Hossein Taghizadeh ◽  
Tamara Braunschmid ◽  
Thomas Bachleitner-Hofmann ◽  
Christine Mannhalter
Keyword(s):  
Colorectal Cancer ◽  
Cancer Patients ◽  
Tumor Burden ◽  
Cell Free Dna ◽  
Free Dna ◽  
Potential Biomarker ◽  
Colorectal Cancer Patients ◽  
Circulating Cell Free Dna
Sign in / Sign up

Export Citation Format

Share Document