6533b7d9fe1ef96bd126cc81
RESEARCH PRODUCT
Genome-wide promoter methylation analysis in neuroblastoma identifies prognostic methylation biomarkers.
Maté OngenaertJo VandesompeleFrank SpelemanRosa NogueraRuth LadensteinGert Van PeerJohannes H. SchulteJoëlle VermeulenAn Van DammeWim Van CriekingeAnneleen DecockGenevieve LaureysKatleen De PreterRaymond L. StallingsRaymond L. StallingsTom Van MaerkenTom Van MaerkenJasmien HoebeeckJasmien Hoebeecksubject
EpigenomicsMYCN Single CopyMedizinPrimary Neuroblastoma TumorBioinformaticsNeuroblastoma0302 clinical medicineRisk FactorsMYCN StatusDatabases GeneticPromoter MethylationGTP-Binding Protein alpha Subunits GsHazard Ratio PatientPromoter Regions GeneticEpigenomicsRegulation of gene expression0303 health sciencesMassive parallel sequencingHigh-Throughput Nucleotide SequencingMethylation3. Good healthGene Expression Regulation NeoplasticMedizinische Fakultät » Universitätsklinikum Essen » Zentrum für Kinder- und Jugendmedizin030220 oncology & carcinogenesisDNA methylationAzacitidineBiologieBiologyDecitabine03 medical and health sciencesneuroblastomaCell Line TumorNeuroblastomaBiomarkers TumorChromograninsmedicineHumansddc:61ddc:610Epigenetics030304 developmental biologyepigeneticsGenome HumanResearchBiology and Life SciencesbiomarkersSequence Analysis DNADNA MethylationHCT116 Cellsmedicine.diseaseSurvival AnalysisCancer researchHuman genomeDNA-methylationdescription
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. © 2012 Decock et al. licensee BioMed Central Ltd.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2012-01-01 |