mFast-SeqS as a Monitoring and Pre-screening Tool for Tumor-Specific Aneuploidy in Plasma DNA

Belic, Jelena; Koch, Marina; Ulz, Peter; Auer, Martina; Gerhalter, Teresa; Mohan, Sumitra; Fischereder, Katja; Petru, Edgar; Bauernhofer, Thomas; Geigl, Jochen B.; Speicher, Michael R.; Heitzer, Ellen

doi:10.1007/978-3-319-42044-8_28

Cited by 26 publications

(20 citation statements)

References 19 publications

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“…Our study shows that an increase in tumor fraction in the plasma by LP-WGS likely reflects tumor progression. Because it is time-and cost-effective, LP-WGS can also be used as an initial quality control step to determine tumor fraction and select only the samples with high tumor fraction to perform target enrichment and deep sequencing (15,20).…”

Section: Discussionmentioning

confidence: 99%

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Low-pass Whole-genome Sequencing of Circulating Cell-free DNA Demonstrates Dynamic Changes in Genomic Copy Number in a Squamous Lung Cancer Clinical Cohort

Chen¹,

Chang²,

Spoerke³

et al. 2019

Clinical Cancer Research

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Purpose: We developed a method to monitor copy number variations (CNV) in plasma cell-free DNA (cfDNA) from patients with metastatic squamous non-small cell lung cancer (NSCLC). We aimed to explore the association between tumor-derived cfDNA and clinical outcomes, and sought CNVs that may suggest potential resistance mechanisms. Experimental Design: Sensitivity and specificity of low-pass whole-genome sequencing (LP-WGS) were first determined using cell line DNA and cfDNA. LP-WGS was performed on baseline and longitudinal cfDNA of 152 patients with squamous NSCLC treated with chemotherapy, or in combination with pictilisib, a pan-PI3K inhibitor. cfDNA tumor fraction and detected CNVs were analyzed in association with clinical outcomes. Results: LP-WGS successfully detected CNVs in cfDNA with tumor fraction !10%, which represented approximately 30% of the first-line NSCLC patients in this study. The most frequent CNVs were gains in chromosome 3q, which harbors the PIK3CA and SOX2 oncogenes. The CNV landscape in cfDNA with a high tumor fraction generally matched that of corresponding tumor tissue. Tumor fraction in cfDNA was dynamic during treatment, and increases in tumor fraction and corresponding CNVs could be detected before radiographic progression in 7 of 12 patients. Recurrent CNVs, such as MYC amplification, were enriched in cfDNA from posttreatment samples compared with the baseline, suggesting a potential resistance mechanism to pictilisib. Conclusions: LP-WGS offers an unbiased and highthroughput way to investigate CNVs and tumor fraction in cfDNA of patients with cancer. It may also be valuable for monitoring treatment response, detecting disease progression early, and identifying emergent clones associated with therapeutic resistance.

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Section: Discussionmentioning

confidence: 99%

“…Over the past 15 years, NGS technology has evolved rapidly and is playing an increasingly important role in cancer research and clinical studies (19). It has been shown that low-pass whole-genome sequencing (LP-WGS) was capable of identifying both focal and broad CNVs in cfDNA from patients with cancer (15,20).…”

Section: Introductionmentioning

confidence: 99%

Low-pass Whole-genome Sequencing of Circulating Cell-free DNA Demonstrates Dynamic Changes in Genomic Copy Number in a Squamous Lung Cancer Clinical Cohort

Chen¹,

Chang²,

Spoerke³

et al. 2019

Clinical Cancer Research

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“…During a median follow-up period of 6 months (range 0.4-19.2), serial plasma samples (median 5, range 2-21) were collected before and during treatment. mFAST-SeqS was used as an initial measure of tumor content [20,37]. For all samples, the median genome-wide z-score was 1.0 (range − 0.9-58.0), and an elevated z-score was observed in 19/252 samples (7.5%) from 9 patients.…”

Section: Longitudinal Analysis Of Ctdna In Renal Tumorsmentioning

confidence: 99%

Comprehensive characterization of cell-free tumor DNA in plasma and urine of patients with renal tumors

et al. 2020

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Background: Cell-free tumor-derived DNA (ctDNA) allows non-invasive monitoring of cancers, but its utility in renal cell cancer (RCC) has not been established. Methods: Here, a combination of untargeted and targeted sequencing methods, applied to two independent cohorts of patients (n = 91) with various renal tumor subtypes, were used to determine ctDNA content in plasma and urine. Results: Our data revealed lower plasma ctDNA levels in RCC relative to other cancers of similar size and stage, with untargeted detection in 27.5% of patients from both cohorts. A sensitive personalized approach, applied to plasma and urine from select patients (n = 22) improved detection to~50%, including in patients with early-stage disease and even benign lesions. Detection in plasma, but not urine, was more frequent amongst patients with larger tumors and in those patients with venous tumor thrombus. With data from one extensively characterized patient, we observed that plasma and, for the first time, urine ctDNA may better represent tumor heterogeneity than a single tissue biopsy. Furthermore, in a subset of patients (n = 16), longitudinal sampling revealed that ctDNA can track disease course and may preempt radiological identification of minimal residual disease or disease progression on systemic therapy. Additional datasets will be required to validate these findings. Conclusions: These data highlight RCC as a ctDNA-low malignancy. The biological reasons for this are yet to be determined. Nonetheless, our findings indicate potential clinical utility in the management of patients with renal tumors, provided improvement in isolation and detection approaches.

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“…Thus, genetic heterogeneity between tumours will be a major limitation for targeted approaches. Analysis of CNAs interrogates the whole genome in a single test method, but often requires at least 3%–10% tumour fraction in plasma cfDNA for reliable detection . It is less likely that early‐stage tumours will shed this much ctDNA.…”

Section: Difficulties and Limitations Of Ctdna Analysismentioning

confidence: 99%

Cell‐free tumour DNA testing for early detection of cancer – a potential future tool

et al. 2019

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In recent years, detection of cell‐free tumour DNA (ctDNA) or liquid biopsy has emerged as an attractive noninvasive methodology to detect cancer‐specific genetic aberrations in plasma, and numerous studies have reported on the feasibility of ctDNA in advanced cancer. In particular, ctDNA assays can capture a more ‘global’ portrait of tumour heterogeneity, monitor therapy response, and lead to early detection of resistance mutations. More recently, ctDNA analysis has also been proposed as a promising future tool for detection of early cancer and/or cancer screening. As the average proportion of mutated DNA in plasma is very low (0.4% even in advanced cancer), exceedingly sensitive techniques need to be developed. In addition, as tumours are genetically heterogeneous, any screening test needs to assay multiple genetic targets in order to increase the chances of detection. Further research on the genetic progression from normal to cancer cells and their release of ctDNA is imperative in order to avoid overtreating benign/indolent lesions, causing more harm than good by early diagnosis. More knowledge on the sources and elimination of cell‐free DNA will enable better interpretation in older individuals and those with comorbidities. In addition, as white blood cells are the major source of cell‐free DNA in plasma, it is important to distinguish acquired mutations in leukocytes (benign clonal haematopoiesis) from an upcoming haematological malignancy or other cancer. In conclusion, although many studies report encouraging results, further technical development and larger studies are warranted before applying ctDNA analysis for early cancer detection in the clinic.

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mFast-SeqS as a Monitoring and Pre-screening Tool for Tumor-Specific Aneuploidy in Plasma DNA

Cited by 26 publications

References 19 publications

Low-pass Whole-genome Sequencing of Circulating Cell-free DNA Demonstrates Dynamic Changes in Genomic Copy Number in a Squamous Lung Cancer Clinical Cohort

Low-pass Whole-genome Sequencing of Circulating Cell-free DNA Demonstrates Dynamic Changes in Genomic Copy Number in a Squamous Lung Cancer Clinical Cohort

Comprehensive characterization of cell-free tumor DNA in plasma and urine of patients with renal tumors

Cell‐free tumour DNA testing for early detection of cancer – a potential future tool

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