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Oncotarget. 2016 Jan 12;7(2):1960-72. doi: 10.18632/oncotarget.6477.

Methyl-CpG-binding domain sequencing reveals a prognostic methylation signature in neuroblastoma.

Author information

1
Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium.
2
Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent, Belgium.
3
Bioinformatics Institute Ghent From Nucleotides to Networks (BIG N2N), De Pintelaan, Ghent, Belgium.
4
DAMBI, VIB Inflammation Research Center, Technologiepark, Ghent, Belgium.
5
Department of Respiratory Medicine, Ghent University, De Pintelaan, Ghent, Belgium.
6
Department of Pediatric Hematology and Oncology, Ghent University Hospital, De Pintelaan, Ghent, Belgium.
7
Department of Pathology, Medical School, University of Valencia, and Health Research Institute INCLIVA, Blasco Ibañez, Valencia, Spain.
8
Department of Pathological Physiology, Department of Pediatric Oncology, Masaryk University, Černopolní, Brno, Czech Republic.
9
Northern Genetics Service, Institute of Genetic Medicine, Central Parkway, Newcastle upon Tyne, United Kingdom.
10
Department of Pediatric Oncology, Institut Curie, rue d'Ulm, Paris, France.
11
Centre Léon Bérard, Laboratoire de Recherche Translationnelle, rue Laennec, Lyon, France.
12
Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick NSW, Australia.
13
Pediatric Hemato-oncology, CHR Citadelle, Liège, Belgium.
14
Unité de Génétique Somatique, Institut Curie, rue d'Ulm, Paris, France.
15
U830 INSERM, Recherche Translationelle en Oncologie Pédiatrique (RTOP) and Department of Pediatric Oncology, Institut Curie, rue d'Ulm, Paris, France.
16
Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Hufelandstraße, Essen, Germany.
17
National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland.
18
Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, York House, Dublin, Ireland.
19
Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle upon Tyne, United Kingdom.

Abstract

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.

KEYWORDS:

DNA methylation; biomarker; neuroblastoma; prognosis

PMID:
26646589
PMCID:
PMC4811509
DOI:
10.18632/oncotarget.6477
[Indexed for MEDLINE]
Free PMC Article

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