title: Genome-wide DNA methylation analysis identifies MEGF10 as a novel epigenetically repressed candidate tumor suppressor gene in neuroblastoma.
abstract: Neuroblastoma is a childhood cancer in which many children still have poor outcomes, emphasising the need to better understand its pathogenesis. Despite recent genome-wide mutation analyses, many primary neuroblastomas do not contain recognizable driver mutations, implicating alternate molecular pathologies such as epigenetic alterations. To discover genes that become epigenetically deregulated during neuroblastoma tumorigenesis, we took the novel approach of comparing neuroblastomas to neural crest precursor cells, using genome-wide DNA methylation analysis. We identified 93 genes that were significantly differentially methylated of which 26 (28%) were hypermethylated and 67 (72%) were hypomethylated. Concentrating on hypermethylated genes to identify candidate tumor suppressor loci, we found the cell engulfment and adhesion factor gene MEGF10 to be epigenetically repressed by DNA hypermethylation or by H3K27/K9 methylation in neuroblastoma cell lines. MEGF10 showed significantly down-regulated expression in neuroblastoma tumor samples; furthermore patients with the lowest-expressing tumors had reduced relapse-free survival. Our functional studies showed that knock-down of MEGF10 expression in neuroblastoma cell lines promoted cell growth, consistent with MEGF10 acting as a clinically relevant, epigenetically deregulated neuroblastoma tumor suppressor gene. © 2016 The Authors. Molecular Carcinogenesis Published by Wiley Periodicals, Inc.
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
authors.forename: Jessica
authors.initials: J
authors.lastname: Charlet
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Tomari
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Dallosso
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
authors.forename: Marianna
authors.initials: M
authors.lastname: Szemes
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
authors.forename: Martina
authors.initials: M
authors.lastname: Kaselova
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Curry
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
authors.forename: Bader
authors.initials: B
authors.lastname: Almutairi
authors.affiliation: Faculté de Médecine, Aix-Marseille University, GMGF, UMR_S910, Marseille, France.|Faculté de Médecine, INSERM U910, Marseille, France.
authors.forename: Heather C
authors.initials: HC
authors.lastname: Etchevers
authors.affiliation: Institute of Cancer & Genomic Sciences, University of Birmingham, UK.
authors.forename: Carmel
authors.initials: C
authors.lastname: McConville
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
authors.forename: Karim T A
authors.initials: KT
authors.lastname: Malik
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
authors.forename: Keith W
authors.initials: KW
authors.lastname: Brown
mesh_terms: D045744:Cell Line, Tumor; D002648:Child; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D042421:Histone Code; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D009447:Neuroblastoma / Q000235:genetics*
chemical_list: C522055:MEGF10, human; D008565:Membrane Proteins
keywords: DNA methylation; MEGF10; epigenetics; histone methylation; neuroblastoma