Sensitive tumour detection and classification using plasma cell-free DNA methylomes

Shen, Shu Yi; Singhania, Rajat; Fehringer, Gordon; Chakravarthy, Ankur; Roehrl, Michael H. A.; Chadwick, Dianne; Zuzarte, Philip C.; Borgida, Ayelet; Wang, Ting Ting; Li, Tiantian; Kis, Olena; Zhao, Zhen; Spreafico, Anna; Medina, Tiago da Silva; Ya-don, Wang; Roulois, David; Ettayebi, Ilias; Chen, Zhuo; Chow, Signy; Murphy, Tracy; Arruda, Andrea; O’Kane, Grainne M.; Liu, Jessica; Mansour, Mark; Mcpherson, John Douglas; O’Brien, Catherine; Leighl, Natasha B.; Bedard, Philippe L.; Fleshner, Neil; Liu, Geoffrey; Minden, Mark D.; Gallinger, Steven; Goldenberg, Anna; Pugh, Trevor J.; Hoffman, Michael M.; Bratman, Scott V.; Hung, Rayjean J.; Carvalho, Daniel D. De

doi:10.1038/s41586-018-0703-0

Cited by 700 publications

(635 citation statements)

References 38 publications

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“…The epigenetic landscape of myeloid malignancies may also have useful information for clinical management. For example, classification of cancer types based on profiling of differentially methylated regions of DNA from cell‐free DNA (cfDNA) from plasma has recently been demonstrated . Myeloid malignancies are also often affected by mutations in epigenetic modifiers such as DNMT3A and TET2 , and hypomethylating agents are standard of care in subsets of patients.…”

Section: What Are the Specific Advantages Of A Transcriptome‐wide Assay?mentioning

confidence: 99%

Genomic testing in myeloid malignancy

Docking

Karsan

2019

Int J Lab Hematology

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Clinical genetic testing in the myeloid malignancies is undergoing a rapid transition from the era of cytogenetics and single‐gene testing to an era dominated by next‐generation sequencing (NGS). This transition promises to better reveal the genetic alterations underlying disease, but there are distinct risks and benefits associated with different NGS testing platforms. NGS offers the potential benefit of being able to survey alterations across a wider set of genes, but analytic and clinical challenges associated with incidental findings, germ line variation, turnaround time, and limits of detection must be addressed. Additionally, transcriptome‐based testing may offer several distinct benefits beyond traditional DNA‐based methods. In addition to testing at disease diagnosis, research indicates potential benefits of genetic testing both prior to disease onset and at remission. In this review, we discuss the transition from the era of cytogenetics and single‐gene tests to the era of NGS panels and genome‐wide sequencing—highlighting both the potential and drawbacks of these novel technologies.

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Section: What Are the Specific Advantages Of A Transcriptome‐wide Assay?mentioning

confidence: 99%

Genomic testing in myeloid malignancy

Docking

Karsan

2019

Int J Lab Hematology

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“…Since cfDNA is only present in the blood in small amounts, as an onerous amount of blood must be extracted from a patient to get the required amount of input DNA for methylation chips, which may not be practical for clinical use [28]. Other technologies and methods focus on sensitive detection of specific tissues or cancer sites [29][30] [31]. While increasingly powerful, these approaches can not provide biomarker discovery or comprehensive deconvolution.…”

Section: Introductionmentioning

confidence: 99%

Estimating the rate of cell type degeneration from epigenetic sequencing of cell-free DNA

Caggiano

Celona

Garton

et al. 2020

Preprint

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Circulating cell-free DNA (cfDNA) in the bloodstream originates from dying cells and is a promising non-invasive biomarker for cell death. Here, we develop a method to accurately estimate the relative abundances of cell types contributing to cfDNA. We leverage the distinct DNA methylation profile of each cell type throughout the body. Decomposing the cfDNA mixture is difficult, as fragments from relevant cell types may only be present in a small amount. We propose an algorithm, CelFiE, that estimates cell type proportion from both whole genome cfDNA input and reference data. CelFiE accommodates low coverage data, does not rely on CpG site curation, and estimates contributions from multiple unknown cell types that are not available in reference data. In simulations we show that CelFiE can accurately estimate known and unknown cell type of origin of cfDNA mixtures in low coverage and noisy data. Simulations also demonstrate that we can effectively estimate cfDNA originating from rare cell types composing less than 0.01% of the total cfDNA. To validate CelFiE, we use a positive control: cfDNA extracted from pregnant and non-pregnant women. CelFiE estimates a large placenta component specifically in pregnant women (p = 9.1 × 10 −5 ). Finally, we use CelFiE to decompose cfDNA from ALS patients and age matched controls. We find increased cfDNA concentrations in ALS patients (p = 3.0 × 10 −3 ). Specifically, CelFiE estimates increased skeletal muscle component in the cfDNA of ALS patients (p = 2.6 × 10 −3 ), which is consistent with muscle impairment characterizing ALS. Quantification of skeletal muscle death in ALS is novel, and overall suggests that CelFiE may be a useful tool for biomarker discovery and monitoring of disease progression.

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“…ctDNA can be detected and quantified by measuring the presence of somatic events, including SNVs, insertion/deletions (indels), copy‐number changes, translocations, and methylation patterns that differentiate tumor DNA from cell‐free DNA originating from normal cells . One recent article demonstrated that methylation patterns in cell‐free DNA can be used to detect the presence of ctDNA and correlate ctDNA methylation with specific cancer histologies . However, this strategy has yet to be applied to pediatric solid tumors.…”

Section: Detection Quantification and Characterization Of Ctdna In mentioning

confidence: 99%

Assessment of circulating tumor DNA in pediatric solid tumors: The promise of liquid biopsies

Abbou

Shulman

DuBois

et al. 2019

Pediatric Blood & Cancer

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Circulating tumor DNA (ctDNA) can be detected in the blood and body fluids of patients using ultra-sensitive technologies which have the potential to improve cancer diagnosis, risk stratification, non-invasive tumor profiling, and tracking of treatment response and disease recurrence. As we begin to apply “liquid biopsy” strategies in children with cancer, it is important to tailor our efforts to the unique genomic features of these tumors and address the technical and logistical challenges of integrating biomarker testing. This article reviews the literature demonstrating the feasibility of applying liquid biopsy to pediatric solid malignancies and suggests new directions for future studies.

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Sensitive tumour detection and classification using plasma cell-free DNA methylomes

Cited by 700 publications

References 38 publications

Genomic testing in myeloid malignancy

Genomic testing in myeloid malignancy

Estimating the rate of cell type degeneration from epigenetic sequencing of cell-free DNA

Assessment of circulating tumor DNA in pediatric solid tumors: The promise of liquid biopsies

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