Genome-wide promoter methylation analysis in neuroblastoma identifies prognostic methylation biomarkers

2.50
Hdl Handle:
http://hdl.handle.net/10147/247115
Title:
Genome-wide promoter methylation analysis in neuroblastoma identifies prognostic methylation biomarkers
Authors:
Decock, Anneleen; Ongenaert, Maté; Hoebeeck, Jasmien; De Preter, Katleen; Van Peer, Gert; Van Criekinge, Wim; Ladenstein, Ruth; Schulte, Johannes H; Noguera, Rosa; Stallings, Raymond L; Van Damme, An; Laureys, Geneviève; Vermeulen, Joëlle; Van Maerken, Tom; Speleman, Frank; Vandesompele, Jo
Citation:
Genome Biology. 2012 Oct 03;13(10):R95
Issue Date:
3-Oct-2012
URI:
http://dx.doi.org/10.1186/gb-2012-13-10-r95; http://hdl.handle.net/10147/247115
Abstract:
Abstract Background Accurate outcome prediction in neuroblastoma, which is necessary to enable the optimal choice of risk-related therapy, remains a challenge. To improve neuroblastoma patient stratification, this study aimed to identify prognostic tumor DNA methylation biomarkers. Results To identify genes silenced by promoter methylation, we first applied two independent genome-wide methylation screening methodologies to eight neuroblastoma cell lines. Specifically, we used re-expression profiling upon 5-aza-2'-deoxycytidine (DAC) treatment and massively parallel sequencing after capturing with a methyl-CpG-binding domain (MBD-seq). Putative methylation markers were selected from DAC-upregulated genes through a literature search and an upfront methylation-specific PCR on 20 primary neuroblastoma tumors, as well as through MBD- seq in combination with publicly available neuroblastoma tumor gene expression data. This yielded 43 candidate biomarkers that were subsequently tested by high-throughput methylation-specific PCR on an independent cohort of 89 primary neuroblastoma tumors that had been selected for risk classification and survival. Based on this analysis, methylation of KRT19, FAS, PRPH, CNR1, QPCT, HIST1H3C, ACSS3 and GRB10 was found to be associated with at least one of the classical risk factors, namely age, stage or MYCN status. Importantly, HIST1H3C and GNAS methylation was associated with overall and/or event-free survival. Conclusions This study combines two genome-wide methylation discovery methodologies and is the most extensive validation study in neuroblastoma performed thus far. We identified several novel prognostic DNA methylation markers and provide a basis for the development of a DNA methylation-based prognostic classifier in neuroblastoma.
Item Type:
Journal Article

Full metadata record

DC FieldValue Language
dc.contributor.authorDecock, Anneleen-
dc.contributor.authorOngenaert, Maté-
dc.contributor.authorHoebeeck, Jasmien-
dc.contributor.authorDe Preter, Katleen-
dc.contributor.authorVan Peer, Gert-
dc.contributor.authorVan Criekinge, Wim-
dc.contributor.authorLadenstein, Ruth-
dc.contributor.authorSchulte, Johannes H-
dc.contributor.authorNoguera, Rosa-
dc.contributor.authorStallings, Raymond L-
dc.contributor.authorVan Damme, An-
dc.contributor.authorLaureys, Geneviève-
dc.contributor.authorVermeulen, Joëlle-
dc.contributor.authorVan Maerken, Tom-
dc.contributor.authorSpeleman, Frank-
dc.contributor.authorVandesompele, Jo-
dc.date.accessioned2012-10-05T09:14:19Z-
dc.date.available2012-10-05T09:14:19Z-
dc.date.issued2012-10-03-
dc.identifier.citationGenome Biology. 2012 Oct 03;13(10):R95-
dc.identifier.urihttp://dx.doi.org/10.1186/gb-2012-13-10-r95-
dc.identifier.urihttp://hdl.handle.net/10147/247115-
dc.description.abstractAbstract Background Accurate outcome prediction in neuroblastoma, which is necessary to enable the optimal choice of risk-related therapy, remains a challenge. To improve neuroblastoma patient stratification, this study aimed to identify prognostic tumor DNA methylation biomarkers. Results To identify genes silenced by promoter methylation, we first applied two independent genome-wide methylation screening methodologies to eight neuroblastoma cell lines. Specifically, we used re-expression profiling upon 5-aza-2'-deoxycytidine (DAC) treatment and massively parallel sequencing after capturing with a methyl-CpG-binding domain (MBD-seq). Putative methylation markers were selected from DAC-upregulated genes through a literature search and an upfront methylation-specific PCR on 20 primary neuroblastoma tumors, as well as through MBD- seq in combination with publicly available neuroblastoma tumor gene expression data. This yielded 43 candidate biomarkers that were subsequently tested by high-throughput methylation-specific PCR on an independent cohort of 89 primary neuroblastoma tumors that had been selected for risk classification and survival. Based on this analysis, methylation of KRT19, FAS, PRPH, CNR1, QPCT, HIST1H3C, ACSS3 and GRB10 was found to be associated with at least one of the classical risk factors, namely age, stage or MYCN status. Importantly, HIST1H3C and GNAS methylation was associated with overall and/or event-free survival. Conclusions This study combines two genome-wide methylation discovery methodologies and is the most extensive validation study in neuroblastoma performed thus far. We identified several novel prognostic DNA methylation markers and provide a basis for the development of a DNA methylation-based prognostic classifier in neuroblastoma.-
dc.titleGenome-wide promoter methylation analysis in neuroblastoma identifies prognostic methylation biomarkers-
dc.typeJournal Article-
dc.language.rfc3066en-
dc.rights.holderAnneleen Decock et al.; licensee BioMed Central Ltd.-
dc.description.versionPeer Reviewed-
dc.date.updated2012-10-03T19:10:44Z-
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