Oncotarget

Research Papers:

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

Anneleen Decock, Maté Ongenaert, Robrecht Cannoodt, Kimberly Verniers, Bram De Wilde, Geneviève Laureys, Nadine Van Roy, Ana P. Berbegall, Julie Bienertova-Vasku, Nick Bown, Nathalie Clément, Valérie Combaret, Michelle Haber, Claire Hoyoux, Jayne Murray, Rosa Noguera, Gaelle Pierron, Gudrun Schleiermacher, Johannes H. Schulte, Ray L. Stallings, Deborah A. Tweddle, for the Children’s Cancer and Leukaemi Group (CCLG), Katleen De Preter, Frank Speleman and Jo Vandesompele _

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Oncotarget. 2016; 7:1960-1972. https://doi.org/10.18632/oncotarget.6477

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Abstract

Anneleen Decock1,2, Maté Ongenaert1, Robrecht Cannoodt1,2,3,4,5, Kimberly Verniers1,2, Bram De Wilde1,2,6, Geneviève Laureys6, Nadine Van Roy1,2, Ana P. Berbegall7, Julie Bienertova-Vasku8, Nick Bown9, Nathalie Clément10, Valérie Combaret11, Michelle Haber12, Claire Hoyoux13, Jayne Murray12, Rosa Noguera7, Gaelle Pierron14, Gudrun Schleiermacher15, Johannes H. Schulte16, Ray L. Stallings17,18, Deborah A. Tweddle19 for the Children’s Cancer and Leukaemia Group (CCLG), Katleen De Preter1,2,3, Frank Speleman1,2 and Jo Vandesompele1,2,3

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

Correspondence to:

Jo Vandesompele, email:

Keywords: neuroblastoma, DNA methylation, prognosis, biomarker

Received: August 03, 2015 Accepted: November 16, 2015 Published: December 06, 2015

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.


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