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Title: Combined genomic and expression microarray analysis of paediatric astrocytoma
Author: Potter, Nicola Emma
ISNI:       0000 0004 2673 6198
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2008
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Although astrocytomas account for 40% of brain tumours in children, little is known about the genetics of these paediatric tumours. Indeed, 85% of low-grade (WHO grade I and II) and 50% of high-grade (WHO grade III and IV) paediatric astrocytoma have a normal karyotype. The aim of this study was to identify non-random genetic aberrations in different grades of paediatric astrocytoma at both the genomic and expression levels. Affymetrix genechip technology and array comparative genomic hybridisation (aCGH) have been used to generate gene expression profiles of 35 paediatric astrocytoma short-term cell cultures of all grades and 19 pilocytic (PA, grade I) biopsies and identify copy number alterations (CNA) in 32 paediatric astrocytoma short-term cell cultures of all grades and 11 pilocytic biopsies. The PAI biopsy samples have a distinct expression profile compared to normal brain with 1844 genes being differentially expressed in all samples. The KEGG pathway most influenced by these genes is antigen processing and presentation, with the majority of genes being up- regulated. Addition pathways altered include PI3K signalling and MAPK signalling. Only single clone CNAs were detected in PAI including alterations at Ip36.32-p36.3, 14ql2 and 22q33.33 which were lost or gained in the majority of samples. The clone at 14ql2 is located in a region of large-scale copy number alteration (LCV). Alterations at this site have been linked to increased risk of paediatric solid tumour development. No known genes are located within the clone site. However, FOXG1B is adjacent to the clone region and is significantly down-regulated in PAI compared to normal brain. Hierarchical clustering of the short-term cultures according to expression profile similarity demonstrated that paediatric astrocytoma can be grouped into low and high-grade tumours by molecular signature. Furthermore, approximately half of paediatric glioblastoma multiforme (GBMIV, grade IV) clustered with 7 adult GBMIV cultures, suggesting that some paediatric GBMIV are genotypically similar to those arising in adults. KEGG pathways influenced by differential gene expression include Wnt signalling and the cell cycle pathway, with the finding that same pathways are being disrupted to varying extents in low and high-grade paediatric astrocytoma. The frequency of CNAs was similar to those previously reported, with gain of all or part of chromosome 7 as the most common alteration. Correlations between gene expression and CNAs were also identified in the short-term cultures.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available