title: Methylation profiling of paediatric pilocytic astrocytoma reveals variants specifically associated with tumour location and predictive of recurrence.
abstract: Childhood pilocytic astrocytomas (PA) are low-grade tumours with an excellent prognosis. However, a minority, particularly those in surgically inaccessible locations, have poorer long-term outcome. At present, it is unclear whether anatomical location in isolation, or in combination with underlying biological variation, determines clinical behaviour. Here, we have tested the utility of DNA methylation profiling to inform tumour biology and to predict behaviour in paediatric PA. Genome-wide DNA methylation profiles were generated for 117 paediatric PAs. Using a combination of analyses, we identified DNA methylation variants specific to tumour location and predictive of behaviour. Receiver-operating characteristic analysis was used to test the predictive utility of clinical and/or DNA methylation features to classify tumour behaviour at diagnosis. Unsupervised analysis distinguished three methylation clusters associated with tumour location (cortical, midline and infratentorial). Differential methylation of 5404 sites identified enrichment of genes involved in 'embryonic nervous system development'. Specific hypermethylation of NEUROG1 and NR2E1 was identified as a feature of cortical tumours. A highly accurate method to classify tumours according to behaviour, which combined three clinical features (age, location and extent of resection) and methylation level at a single site, was identified. Our findings show location-specific epigenetic profiles for PAs, potentially reflecting their cell type of origin. This may account for differences in clinical behaviour according to location independent of histopathology. We also defined an accurate method to predict tumour behaviour at diagnosis. This warrants further testing in similar patient cohorts.
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Australia.|Department of Paediatrics, The University of Melbourne, Parkville, Australia.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Sexton-Oates
authors.affiliation: Children's Cancer Centre, The Royal Children's Hospital, Parkville, Australia.|Department of Paediatrics, University of Otago, Christchurch, New Zealand.
authors.forename: Andrew
authors.initials: A
authors.lastname: Dodgshun
authors.affiliation: Division of Molecular Genetics, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Hovestadt
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors.forename: David T W
authors.initials: DTW
authors.lastname: Jones
authors.affiliation: School of Medicine, Deakin University, Waurn Ponds, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Ashley
authors.affiliation: Department of Paediatrics, The University of Melbourne, Parkville, Australia.|Children's Cancer Centre, The Royal Children's Hospital, Parkville, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Sullivan
authors.affiliation: Department of Anatomical Pathology, The Royal Children's Hospital, Parkville, Australia.|Department of Pathology, The University of Melbourne, Parkville, Australia.
authors.forename: Duncan
authors.initials: D
authors.lastname: MacGregor
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Australia.|Department of Paediatrics, The University of Melbourne, Parkville, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Saffery
mesh_terms: D001254:Astrocytoma / Q000175:diagnosis* / Q000235:genetics; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000235:genetics; D002648:Child; D019175:DNA Methylation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000235:genetics; D057093:Orphan Nuclear Receptors; D011379:Prognosis; D000077982:Progression-Free Survival; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics
chemical_list: C088601:NR2E1 protein, human; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: DNA methylation; pilocytic astrocytoma