title: Aberrant methylation of candidate tumor suppressor genes in neuroblastoma.
abstract: CpG island hypermethylation has been recognized as an alternative mechanism for tumor suppressor gene inactivation. In this study, we performed methylation-specific PCR (MSP) to investigate the methylation status of 10 selected tumor suppressor genes in neuroblastoma. Seven of the investigated genes (CD44, RASSF1A, CASP8, PTEN, ZMYND10, CDH1, PRDM2) showed high frequencies (> or =30%) of methylation in 33 neuroblastoma cell lines. In 42 primary neuroblastoma tumors, the frequencies of methylation were 69%, CD44; 71%, RASSF1A; 56%, CASP8; 25%, PTEN; 15%, ZMYND10; 8%, CDH1; and 0%, PRDM2. Furthermore, CASP8 and CDH1 hypermethylation was significantly associated with poor event-free survival. Meta-analysis of 115 neuroblastoma tumors demonstrated a significant correlation between CASP8 methylation and MYCN amplification. In addition, there was a correlation between ZMYND10 methylation and MYCN amplification. The MSP data, together with optimized mRNA re-expression experiments (in terms of concentration and time of treatment and use of proper reference genes) further strengthen the notion that epigenetic alterations could play a significant role in NB oncogenesis. This study thus warrants the need for a global profiling of gene promoter hypermethylation to identify genome-wide aberrantly methylated genes in order to further understand neuroblastoma pathogenesis and to identify prognostic methylation markers.
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Jasmien
authors.initials: J
authors.lastname: Hoebeeck
authors.forename: Evi
authors.initials: E
authors.lastname: Michels
authors.forename: Filip
authors.initials: F
authors.lastname: Pattyn
authors.forename: Valérie
authors.initials: V
authors.lastname: Combaret
authors.forename: Joëlle
authors.initials: J
authors.lastname: Vermeulen
authors.forename: Nurten
authors.initials: N
authors.lastname: Yigit
authors.forename: Claire
authors.initials: C
authors.lastname: Hoyoux
authors.forename: Geneviève
authors.initials: G
authors.lastname: Laureys
authors.forename: Anne
authors.initials: A
authors.lastname: De Paepe
authors.forename: Frank
authors.initials: F
authors.lastname: Speleman
authors.forename: Jo
authors.initials: J
authors.lastname: Vandesompele
mesh_terms: D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D000077209:Decitabine; D044127:Epigenesis, Genetic; D016147:Genes, Tumor Suppressor; D016678:Genome; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007223:Infant; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D006877:Hydroxamic Acids; D012333:RNA, Messenger; C012589:trichostatin A; D000077209:Decitabine; D001374:Azacitidine