title: DNA methylation analysis of paediatric low-grade astrocytomas identifies a tumour-specific hypomethylation signature in pilocytic astrocytomas.
abstract: Low-grade gliomas (LGGs) account for about a third of all brain tumours in children. We conducted a detailed study of DNA methylation and gene expression to improve our understanding of the biology of pilocytic and diffuse astrocytomas. Pilocytic astrocytomas were found to have a distinctive signature at 315 CpG sites, of which 312 were hypomethylated and 3 were hypermethylated. Genomic analysis revealed that 182 of these sites are within annotated enhancers. The signature was not present in diffuse astrocytomas, or in published profiles of other brain tumours and normal brain tissue. The AP-1 transcription factor was predicted to bind within 200 bp of a subset of the 315 differentially methylated CpG sites; the AP-1 factors, FOS and FOSL1 were found to be up-regulated in pilocytic astrocytomas. We also analysed splice variants of the AP-1 target gene, CCND1, which encodes cell cycle regulator cyclin D1. CCND1a was found to be highly expressed in both pilocytic and diffuse astrocytomas, but diffuse astrocytomas have far higher expression of the oncogenic variant, CCND1b. These findings highlight novel genetic and epigenetic differences between pilocytic and diffuse astrocytoma, in addition to well-described alterations involving BRAF, MYB and FGFR1.
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, E1 2AT, UK.
authors.forename: Jennie N
authors.initials: JN
authors.lastname: Jeyapalan
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, E1 2AT, UK.
authors.forename: Gabriel T
authors.initials: GT
authors.lastname: Doctor
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, E1 2AT, UK.
authors.forename: Tania A
authors.initials: TA
authors.lastname: Jones
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, E1 2AT, UK.
authors.forename: Samuel N
authors.initials: SN
authors.lastname: Alberman
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, E1 2AT, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Tep
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, E1 2AT, UK.
authors.forename: Chirag M
authors.initials: CM
authors.lastname: Haria
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.|Department of Applied Sciences, Northumbria University, Newcastle upon Tyne, UK.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Schwalbe
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, E1 2AT, UK.
authors.forename: Isabel C F
authors.initials: IC
authors.lastname: Morley
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, E1 2AT, UK.
authors.forename: Alfred A
authors.initials: AA
authors.lastname: Hill
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, E1 2AT, UK.
authors.forename: Magdalena
authors.initials: M
authors.lastname: LeCain
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, E1 2AT, UK.
authors.forename: Diego
authors.initials: D
authors.lastname: Ottaviani
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Clifford
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Qaddoumi
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, 38105-3678, USA.
authors.forename: Ruth G
authors.initials: RG
authors.lastname: Tatevossian
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, 38105-3678, USA. david.ellison@stjude.org.
authors.forename: David W
authors.initials: DW
authors.lastname: Ellison
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, E1 2AT, UK. d.sheer@qmul.ac.uk.
authors.forename: Denise
authors.initials: D
authors.lastname: Sheer
mesh_terms: D000293:Adolescent; D000328:Adult; D001254:Astrocytoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D018899:CpG Islands; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D011401:Promoter Regions, Genetic; D018808:Transcription Factor AP-1 / Q000378:metabolism; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C530104:CCND1 protein, human; D018808:Transcription Factor AP-1; D019938:Cyclin D1
keywords: AP-1 targets; Cyclin D1; Diffuse astrocytomas; Enhancers; FOS; MAPK pathway