Dataset Information

5-Hydroxymethylcytosine Profiles in Circulating Cell-Free DNA Associate with Disease Burden in Children with Neuroblastoma.

ABSTRACT: PURPOSE:5-Hydroxymethylcytosine (5-hmC) is an epigenetic marker of open chromatin and active gene expression. We profiled 5-hmC with Nano-hmC-Seal technology using 10 ng of plasma-derived cell-free DNA (cfDNA) in blood samples from patients with neuroblastoma to determine its utility as a biomarker. EXPERIMENTAL DESIGN:For the Discovery cohort, 100 5-hmC profiles were generated from 34 well children and 32 patients (27 high-risk, 2 intermediate-risk, and 3 low-risk) at various time points during the course of their disease. An independent Validation cohort encompassed 5-hmC cfDNA profiles (n = 29) generated from 21 patients (20 high-risk and 1 intermediate-risk). Metastatic burden was classified as high, moderate, low, or none per Curie metaiodobenzylguanidine scores and percentage of tumor cells in bone marrow. Genes with differential 5-hmC levels between samples according to metastatic burden were identified using DESeq2. RESULTS:Hierarchical clustering using 5-hmC levels of 347 genes identified from the Discovery cohort defined four clusters of samples that were confirmed in the Validation cohort and corresponded to high, high-moderate, moderate, and low/no metastatic burden. Samples from patients with increased metastatic burden had increased 5-hmC deposition on genes in neuronal stem cell maintenance and epigenetic regulatory pathways. Further, 5-hmC cfDNA profiles generated with 1,242 neuronal pathway genes were associated with subsequent relapse in the cluster of patients with predominantly low or no metastatic burden (sensitivity 65%, specificity 75.6%). CONCLUSIONS:cfDNA 5-hmC profiles in children with neuroblastoma correlate with metastatic burden and warrants development as a biomarker of treatment response and outcome.

SUBMITTER: Applebaum MA

PROVIDER: S-EPMC7073281 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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5-Hydroxymethylcytosine Profiles in Circulating Cell-Free DNA Associate with Disease Burden in Children with Neuroblastoma.

Applebaum Mark A MA Barr Erin K EK Karpus Jason J West-Szymanski Diana C DC Oliva Meritxell M Sokol Elizabeth A EA Zhang Sheng S Zhang Zhou Z Zhang Wei W Chlenski Alexandre A Salwen Helen R HR Wilkinson Emma E Dobratic Marija M Grossman Robert L RL Godley Lucy A LA Stranger Barbara E BE He Chuan C Cohn Susan L SL

Clinical cancer research : an official journal of the American Association for Cancer Research 20191218 6

<h4>Purpose</h4>5-Hydroxymethylcytosine (5-hmC) is an epigenetic marker of open chromatin and active gene expression. We profiled 5-hmC with Nano-hmC-Seal technology using 10 ng of plasma-derived cell-free DNA (cfDNA) in blood samples from patients with neuroblastoma to determine its utility as a biomarker.<h4>Experimental design</h4>For the Discovery cohort, 100 5-hmC profiles were generated from 34 well children and 32 patients (27 high-risk, 2 intermediate-risk, and 3 low-risk) at various tim ...[more]

PMID: 31852832

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Project description:Simple Summary The invasive nature of surgical biopsies prevents their sequential application to monitor disease. Single biopsies fail to reflect cancer dynamics, intratumor heterogeneity, and drug sensitivities that change over time. Detection and characterization of cell-free circulating tumor DNA in biofluids from patients with solid tumors may better support disease monitoring and provide advanced molecular information for clinical decision-making toward personalized medicine. Here, we investigated the cell-free DNA characteristics in blood, bone marrow, cerebrospinal fluid, and urine provided from 84 infants and children with low-, intermediate-, or high-risk neuroblastoma. We report characteristic size distribution and concentration patterns for each biofluid to provide information to support the development of successful liquid biopsy biobanking strategies. We investigate potential correlations between disease activity and cfDNA concentration and provide strong evidence that markers specific for neuroblastoma can be detected in very small blood volumes from infants. Abstract Liquid biopsy strategies in pediatric patients are challenging due to low body weight. This study investigated cfDNA size distribution and concentration in blood, bone marrow, cerebrospinal fluid, and urine from 84 patients with neuroblastoma classified as low (n = 28), intermediate (n = 6), or high risk (n = 50) to provide key data for liquid biopsy biobanking strategies. The average volume of blood and bone marrow plasma provided ranged between 1 and 2 mL. Analysis of 637 DNA electropherograms obtained by Agilent TapeStation measurement revealed five different major profiles and characteristic DNA size distribution patterns for each of the biofluids. The proportion of samples containing primarily cfDNA was, at 85.5%, the highest for blood plasma. The median cfDNA concentration amounted to 6.28 ng/mL (blood plasma), 58.2 ng/mL (bone marrow plasma), 0.08 ng/mL (cerebrospinal fluid), and 0.49 ng/mL (urine) in samples. Meta-analysis of the dataset demonstrated that multiple cfDNA-based assays employing the same biofluid sample optimally require sampling volumes of 1 mL for blood and bone marrow plasma, 2 mL for cerebrospinal fluid, and as large as possible for urine samples. A favorable response to treatment was associated with a rapid decrease in blood-based cfDNA concentration in patients with high-risk neuroblastoma. Blood-based cfDNA concentration was not sufficient as a single parameter to indicate high-risk disease recurrence. We provide proof of concept that monitoring neuroblastoma-specific markers in very small blood volumes from infants is feasible.

Dataset Information

5-Hydroxymethylcytosine Profiles in Circulating Cell-Free DNA Associate with Disease Burden in Children with Neuroblastoma.

Publications

5-Hydroxymethylcytosine Profiles in Circulating Cell-Free DNA Associate with Disease Burden in Children with Neuroblastoma.

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