Circulating tumour DNA sequence analysis as an alternative to multiple myeloma bone marrow aspirates

Kis, Olena; Kaedbey, Rayan; Chow, Signy; Danesh, Arnavaz; Dowar, Mark; Li, Tiantian; Li, Zhihua; Liu, Jessica; Mansour, Mark; Masih‐Khan, Esther; Zhang, Tong; Bratman, Scott V.; Oza, Amit M.; Kamel‐Reid, Suzanne; Trudel, Suzanne; Pugh, Trevor J.

doi:10.1038/ncomms15086

Cited by 112 publications

(121 citation statements)

References 38 publications

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“…An important factor is yield of cfDNA. We observed high intra‐ and inter‐patient variability (range 1.75‐405.6 ng per mL of serum), which is consistent with previous studies among MM patients and other malignancies . A wide range of biological and physiological factors, including tumor burden, disease stage or even half‐life of cfDNA can influence release and clearance of tumor‐specific fraction of total cfDNA and play a role in this variability .…”

Section: Discussionsupporting

confidence: 88%

“…Analysis of tumor-specific cfDNA is a promising, emerging form of liquid biopsy in hematological malignancies. 26 So far, several studies investigated cfDNA in MM patients, [27][28][29][30] but only limited long-term data are available. Here, we performed a long-term comprehensive study of cfDNA dynamics, which extends previous findings about applicability of cfDNA analysis for minimally invasive testing of MM patients.…”

Section: Discussionmentioning

confidence: 99%

“…We observed high intra-and inter-patient variability (range 1.75-405.6 ng per mL of serum), which is consistent with previous studies among MM patients and other malignancies. 28 A wide range of biological and physiological factors, including tumor burden, disease stage or even half-life of cfDNA can influence release and clearance of tumor-specific fraction of total cfDNA and play a role in this variability. 42 As a result, scarce amounts of cfDNA are isolated in some cases in which target molecules may be under-represented causing false-negative results.…”

Section: Discussionmentioning

confidence: 99%

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Dynamics of tumor‐specific cfDNA in response to therapy in multiple myeloma patients

Vrábel

Sedlaříková

Besse

et al. 2019

European J of Haematology

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Objectives Progress in multiple myeloma treatment allows patients to achieve deeper responses, for which the assessment of minimal residual disease (MRD) is critical. Typically, bone marrow samples are used for this purpose; however, this approach is site‐limited. Liquid biopsy represents a minimally invasive and more comprehensive technique that is not site‐limited, but equally challenging. Methods While majority of current data comes from short‐term studies, we present a long‐term study on blood‐based MRD monitoring using tumor‐specific cell‐free DNA detection by ASO‐qPCR. One hundred and twelve patients were enrolled into the study, but long‐term sampling and analysis were feasible only in 45 patients. Results We found a significant correlation of quantity of tumor‐specific cell‐free DNA levels with clinically meaningful events [induction therapy (P = .004); ASCT (P = .012)]. Moreover, length of cfDNA fragments is associated with better treatment response of patients. Conclusions These results support the concept of tumor‐specific cell‐free DNA as a prognostic marker.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Dynamics of tumor‐specific cfDNA in response to therapy in multiple myeloma patients

Vrábel

Sedlaříková

Besse

et al. 2019

European J of Haematology

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“…Ultra-deep sequencing of cfDNA isolated from blood plasma ( Figure 1) has recently been shown to recapitulate mutational profiles and relative subclonal composition inferred from clinical testing of matched BM aspirates (96% sensitivity, 100% specificity) (47). In this study, hybrid capture of all exons of five genes in cfDNA followed by sequencing to >20,000X, detected mutations that were not present in single BM aspirates, but that persisted in serial blood samples at concentrations consistent with clinical course.…”

Section: Emerging Technologies-comprehensive Profiling Of Myeloma Fromentioning

confidence: 99%

The Role of Minimal Residual Disease Testing in Myeloma Treatment Selection and Drug Development: Current Value and Future Applications

Anderson

Auclair

Kelloff

et al. 2017

Clinical Cancer Research

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Treatment of myeloma has benefited from the introduction of more effective and better tolerated agents, improvements in supportive care, better understanding of disease biology, revision of diagnostic criteria, and new sensitive and specific tools for disease prognostication and management. Assessment of minimal residual disease (MRD) in response to therapy is one of these tools, as longer progression-free survival (PFS) is seen consistently among patients who have achieved MRD negativity. Current therapies lead to unprecedented frequency and depth of response, and next-generation flow and sequencing methods to measure MRD in bone marrow are in use and being developed with sensitivities in the range of 10 to 10 cells. These technologies may be combined with functional imaging to detect MRD outside of bone marrow. Moreover, immune profiling methods are being developed to better understand the immune environment in myeloma and response to immunomodulatory agents while methods for molecular profiling of myeloma cells and circulating DNA in blood are also emerging. With the continued development and standardization of these methodologies, MRD has high potential for use in gaining new drug approvals in myeloma. The FDA has outlined two pathways by which MRD could be qualified as a surrogate endpoint for clinical studies directed at obtaining accelerated approval for new myeloma drugs. Most importantly, better understanding of MRD should also contribute to better treatment monitoring. Potentially, MRD status could be used as a prognostic factor for making treatment decisions and for informing timing of therapeutic interventions. .

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“…We took advantage of two features in designing the parallelization module. First, we required that added CNVs are independent for each chromosome (although nested events can likely be engineered through serial application of Bamgineer To demonstrate feasibility beyond exome data, we next evaluated these same metrics in a targeted 5-gene panel applied to a cell-free DNA sequencing library generated from a healthy blood donor and sequenced to >10,000X coverage [17] To simulate concentrations of tumorderived fragments typically encountered in cancer patients, we introduced EGFR amplifications at frequencies of 100, 10, 1, 0.1, and 0.01%. As with the exome data, we observed highly specific shifts in allele variant ratios, log2 coverage ratios, and haplotype representation consistent with the targeted allele frequencies.…”

Section: Runtime and Parallelizationmentioning

confidence: 99%

Bamgineer: Introduction of simulated allele-specific copy number variants into exome and targeted sequence data sets

Samadian

Bruce

Pugh

2017

Preprint

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Somatic copy number variations (CNVs) play a crucial role in development of many human cancers. The broad availability of next-generation sequencing data has enabled the development of algorithms to computationally infer CNV profiles from a variety of data types including exome and targeted sequence data; currently the most prevalent types of cancer genomics data.However, systemic evaluation and comparison of these tools remains challenging due to a lack of ground truth reference sets. To address this need, we have developed Bamgineer, a tool written in Python to introduce user-defined haplotype-phased allele-specific copy number events into an existing Binary Alignment Mapping (BAM) file, with a focus on targeted and exome sequencing experiments. As input, this tool requires a read alignment file (BAM format), lists of non-overlapping genome coordinates for introduction of gains and losses (bed file), and an optional file defining known haplotypes (vcf format). To improve runtime performance, Bamgineer introduces the desired CNVs in parallel using queuing and parallel processing on a local machine or on a high-performance computing cluster. As proof-of-principle, we applied Bamgineer to a single high-coverage (mean: 220X) exome sequence file from a blood sample to simulate copy number profiles of 3 exemplar tumors from each of 10 tumor types at 5 tumor cellularity levels (20-100%, 150 BAM files in total). To demonstrate feasibility beyond exome data, we introduced read alignments to a targeted 5-gene cell-free DNA sequencing library to simulate EGFR amplifications at frequencies consistent with circulating tumor DNA (10, 1, 0.1 and 0.01%) while retaining the multimodal insert size distribution of the original data. We expect Bamgineer to be of use for development and systematic benchmarking of CNV calling algorithms by users using locally-generated data for a variety of applications. The source code is freely available at http://github.com/pughlab/bamgineer.

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Circulating tumour DNA sequence analysis as an alternative to multiple myeloma bone marrow aspirates

Cited by 112 publications

References 38 publications

Dynamics of tumor‐specific cfDNA in response to therapy in multiple myeloma patients

Dynamics of tumor‐specific cfDNA in response to therapy in multiple myeloma patients

The Role of Minimal Residual Disease Testing in Myeloma Treatment Selection and Drug Development: Current Value and Future Applications

Bamgineer: Introduction of simulated allele-specific copy number variants into exome and targeted sequence data sets

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