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

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Authors

DECOCK Anneleen ONGENAERT Maté CANNOODT Robrecht VERNIERS Kimberly DE WILDE Bram LAUREYS Genevieve VAN ROY Nadine BERBEGALL Ana P. BIENERTOVÁ VAŠKŮ Julie BOWN Nick CLEMENT Nathalie COMBARET Valérie HABER Michelle HOYOUX Claire MURRAY Jayne NOGUERA Rosa PIERRON Gaelle SCHLEIERMACHER Gudrun SCHULTE Johannes H. STALLINGS Ray L. TWEDDLE Deborah A. DE PRETER Katleen SPELEMAN Frank VANDESOMPELE Jo

Year of publication 2016
Type Article in Periodical
Magazine / Source Oncotarget
MU Faculty or unit

Faculty of Medicine

Citation
Field Oncology and hematology
Keywords neuroblastoma; DNA methylation; prognosis; biomarker
Attached files
Description 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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