Genomic and epigenetic characterisation of childhood ependymoma.
PhD thesis, University of Nottingham.
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Paediatric ependymomas remain a clinical management challenge, with a relatively poor prognosis when compared to other childhood tumours of the central nervous system. An improved understanding of underlying ependymoma biology may identify new correlates of outcome and potential therapeutic targets. To address this, AffymetrixTM 500K SNP arrays were used to establish the nature and range of genomic imbalances in 63 paediatric ependymomas (42 primary and 21 recurrent). Over 80 % of tumours were analysed against patient-matched constitutional DNA. In addition, the Illumina® GoldenGate® Cancer Panel I array was used to identify differences in methylation profile across 98 paediatric ependymomas (73 primary and 25 recurrent). While collective assessment revealed the most common anomalies, specific aberrations were characteristic of certain ependymoma subgroups, particularly those relating to tumour location, patient age, disease recurrence and patient prognosis. The genomic imbalance of 15 selected candidate genes (NSL1, DNAJC25, NAV1, CDKN2A, CHI3L1, HOXA5, TXN, BNIPL, and PRUNE) were confirmed by quantitative Polymerase Chain Reaction. Genomic gain involving regions of chromosome 1q were associated with an unfavourable patient outcome, such as the focal locus on 1q21.3 encompassing PRUNE. The genomic gain of PRUNE correlated with an increased encoded protein expression, as assessed by immunohistochemistry (IHC).
This adverse prognostic association with 1q was upheld in the subsequent part of this work. Fluorescent in situ hybridisation and IHC were used to evaluate a panel of six putative prognostic markers (1q25 gain, PRUNE, Tenascin-C, Nucleolin, Ki-67 and NAV1 expression) across a paediatric intracranial ependymoma tissue microarray cohort of 107 primary tumours treated within the confines of two aged defined clinical trials (UK CCLG 1992 04 and SIOP 1999 04). Within the younger UK CCLG 1992 04 cohort, copy number gain of chromosome 1q25 and PRUNE overexpression were independently associated with an increased risk of disease progression, while strong PRUNE expression was also an independent marker of worse overall survival. In addition, increased Tenascin-C expression correlated with a reduced overall survival on univariate analysis. For older children in the SIOP 1999 04 cohort, strong PRUNE expression in ependymomas was again identified as an adverse prognostic marker, correlating with increased mortality on univariate assessment.
Thesis (University of Nottingham only)
||W Medicine and related subjects (NLM Classification) > WL Nervous system
||UK Campuses > Faculty of Medicine and Health Sciences > School of Clinical Sciences
||18 May 2012 12:10
||08 Dec 2016 02:20
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