title: Adult grade II diffuse astrocytomas are genetically distinct from and more aggressive than their paediatric counterparts.
abstract: Diffuse astrocytomas (WHO grade II) typically present as slow-growing tumours showing significant cellular differentiation, but possessing a tendency towards malignant progression. They account for ~10% of all astrocytic tumours, with a peak incidence between 30 and 40 years of age. Median survival is reported as around 6-8 years. Mutations of TP53 and IDH1 have been described as genetic hallmarks, while copy number alterations are also relatively common. However, there is some evidence to suggest that these characteristics may vary with age. Here, we present an integrated clinicopathologic, genomic and transcriptomic analysis suggesting that paediatric and adult tumours are associated with distinct genetic signatures. For example, no childhood tumour showed mutation of IDH1/2 or TP53, virtually no copy number changes were seen, and MGMT methylation was absent. In contrast, adult tumours showed IDH1/2 mutation in 94% and TP53 mutation in 69% of cases, with multiple copy number alterations per case and hypermethylation of MGMT in the majority of tumours. These differences were associated with a worse prognosis in the adult patients. The expression array data also revealed a significant difference in the expression of a number of genes putatively involved in neural stem cell maintenance and CNS development, including DLL3, HES5, BMP2, TIMP1 and BAMBI. Genes involved in DNA replication and the cell cycle were also enriched in the adult tumours, suggesting that their more aggressive behaviour may be due to derivation from a more rapidly dividing, less differentiated cell type.
authors.affiliation: Division of Molecular Histopathology, Department of Pathology, University of Cambridge, UK. davidjones@cantab.net
authors.forename: David T W
authors.initials: DT
authors.lastname: Jones
authors.forename: Shani A
authors.initials: SA
authors.lastname: Mulholland
authors.forename: Danita M
authors.initials: DM
authors.lastname: Pearson
authors.forename: Deborah S
authors.initials: DS
authors.lastname: Malley
authors.forename: Samuel W S
authors.initials: SW
authors.lastname: Openshaw
authors.forename: Sally R
authors.initials: SR
authors.lastname: Lambert
authors.forename: Lu
authors.initials: L
authors.lastname: Liu
authors.forename: L Magnus
authors.initials: LM
authors.lastname: Bäcklund
authors.forename: Koichi
authors.initials: K
authors.lastname: Ichimura
authors.forename: V Peter
authors.initials: VP
authors.lastname: Collins
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D001254:Astrocytoma / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D002648:Child; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods; D045643:DNA Repair Enzymes / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D025341:Principal Component Analysis; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes