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

Lookup NU author(s): Professor Deborah Tweddle


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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.

Publication metadata

Author(s): Decock A, Ongenaert M, Cannoodt R, Verniers K, De Wilde B, Laureys G, Van Roy N, Berbegall AP, Bienertova-Vasku J, Bown N, Clement N, Combaret V, Haber M, Hoyoux C, Murray J, Noguera R, Pierron G, Schleiermacher G, Schulte JH, Stallings RL, Tweddle DA, De Preter K, Speleman F, Vandesompele J, CCLG

Publication type: Article

Publication status: Published

Journal: Oncotarget

Year: 2016

Volume: 7

Issue: 2

Pages: 1960-1972

Print publication date: 01/01/2016

Online publication date: 06/12/2015

Acceptance date: 16/11/2015

ISSN (print): 1949-2553

Publisher: Impact Journals LLC


DOI: 10.18632/oncotarget.6477


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Funder referenceFunder name
CCLG Centres
Children's Medical and Research Foundation
ECMC Paediatric Network
Emmanuel Van der Schueren research grant (VLK)
Flemish League Against Cancer (VLK)
Institute of Health Carlos III (ISCIII)
Ligue Nationale Contre le Cancer
National Health and Medical Research Council (Australia)
Research Foundation Flanders (FWO)
Annenberg Foundation
Belgian National Lottery
Cancer Institute NSW
Cancer Research UK
European Regional Development Fund (ERDF)
Fournier-Majoie Foundation (FFM)
Spanish Health Research Fund (FIS)
01G01910UGent GOA
07/IN.1/B1776Science Foundation Ireland
2014/01008Thematic Network of Cooperative Research on Cancer (RTICC)
5R01CA127496National Institutes of Health (NIH)
RD12/0036/0020Thematic Network of Cooperative Research on Cancer (RTICC)