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

Autor:	Applebaum MA; Department of Pediatrics, University of Chicago, Chicago, Illinois. mapplebaum@peds.bsd.uchicago.edu., Barr EK; Department of Pediatrics, Texas Tech University Health Sciences, Lubbock, Texas., Karpus J; Department of Chemistry, University of Chicago, Chicago, Illinois., West-Szymanski DC; Department of Medicine, University of Chicago, Chicago, Illinois., Oliva M; Department of Medicine, University of Chicago, Chicago, Illinois., Sokol EA; Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois., Zhang S; Department of Chemistry, University of Chicago, Chicago, Illinois., Zhang Z; Department of Preventive Medicine, Northwestern University, Chicago, Illinois., Zhang W; Department of Preventive Medicine, Northwestern University, Chicago, Illinois., Chlenski A; Department of Pediatrics, University of Chicago, Chicago, Illinois., Salwen HR; Department of Pediatrics, University of Chicago, Chicago, Illinois., Wilkinson E; Department of Pediatrics, University of Chicago, Chicago, Illinois., Dobratic M; Department of Pediatrics, University of Chicago, Chicago, Illinois., Grossman RL; Institute for Genomics and Systems Biology, Center for Translational Data Science, University of Chicago, Chicago, Illinois., Godley LA; Department of Medicine, University of Chicago, Chicago, Illinois., Stranger BE; Department of Medicine, University of Chicago, Chicago, Illinois., He C; Department of Chemistry, University of Chicago, Chicago, Illinois.; Howard Hughes Medical Institute, Chevy Chase, Maryland., Cohn SL; Department of Pediatrics, University of Chicago, Chicago, Illinois.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2020 Mar 15; Vol. 26 (6), pp. 1309-1317. Date of Electronic Publication: 2019 Dec 18.
DOI:	10.1158/1078-0432.CCR-19-2829
Abstrakt:	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. (©2019 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu