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Methyl-CpG-binding domain sequencing reveals a prognostic methylation signature in neuroblastoma
A. Decock, M. Ongenaert, R. Cannoodt, K. Verniers, B. De Wilde, G. Laureys, N. Van Roy, AP. Berbegall, J. Bienertova-Vasku, N. Bown, N. Clément, V. Combaret, M. Haber, C. Hoyoux, J. Murray, R. Noguera, G. Pierron, G. Schleiermacher, JH. Schulte,...
Language English Country United States
Document type Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
NLK
Free Medical Journals
from 2010
PubMed Central
from 2010
Europe PubMed Central
from 2010
Open Access Digital Library
from 2010-01-01
- MeSH
- Biomarkers analysis MeSH
- CpG Islands genetics MeSH
- DNA, Neoplasm genetics MeSH
- Cohort Studies MeSH
- Infant MeSH
- Real-Time Polymerase Chain Reaction MeSH
- Humans MeSH
- DNA Methylation * MeSH
- Tumor Cells, Cultured MeSH
- Neuroblastoma diagnosis genetics MeSH
- Prognosis MeSH
- Neoplasm Staging MeSH
- Binding Sites MeSH
- Computational Biology MeSH
- Check Tag
- Infant MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
Accurate assessment of neuroblastoma outcome prediction remains challenging. Therefore, this study aims at establishing novel prognostic tumor DNA methylation biomarkers. In total, 396 low- and high-risk primary tumors were analyzed, of which 87 were profiled using methyl-CpG-binding domain (MBD) sequencing for differential methylation analysis between prognostic patient groups. Subsequently, methylation-specific PCR (MSP) assays were developed for 78 top-ranking differentially methylated regions and tested on two independent cohorts of 132 and 177 samples, respectively. Further, a new statistical framework was used to identify a robust set of MSP assays of which the methylation score (i.e. the percentage of methylated assays) allows accurate outcome prediction. Survival analyses were performed on the individual target level, as well as on the combined multimarker signature. As a result of the differential DNA methylation assessment by MBD sequencing, 58 of the 78 MSP assays were designed in regions previously unexplored in neuroblastoma, and 36 are located in non-promoter or non-coding regions. In total, 5 individual MSP assays (located in CCDC177, NXPH1, lnc-MRPL3-2, lnc-TREX1-1 and one on a region from chromosome 8 with no further annotation) predict event-free survival and 4 additional assays (located in SPRED3, TNFAIP2, NPM2 and CYYR1) also predict overall survival. Furthermore, a robust 58-marker methylation signature predicting overall and event-free survival was established. In conclusion, this study encompasses the largest DNA methylation biomarker study in neuroblastoma so far. We identified and independently validated several novel prognostic biomarkers, as well as a prognostic 58-marker methylation signature.
Center for Medical Genetics Ghent University De Pintelaan Ghent Belgium
Centre Léon Bérard Laboratoire de Recherche Translationnelle rue Laennec Lyon France
Children's Cancer Institute Lowy Cancer Research Centre UNSW Randwick NSW Australia
Department of Pediatric Hematology and Oncology Ghent University Hospital De Pintelaan Ghent Belgium
Department of Pediatric Oncology Institut Curie rue d'Ulm Paris France
Pediatric Hemato oncology CHR Citadelle Liège Belgium
Unité de Génétique Somatique Institut Curie rue d'Ulm Paris France
References provided by Crossref.org
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