Characterisation of genetic and epigenetic aberrations in paediatric high grade glioma

3.00
Hdl Handle:
http://hdl.handle.net/2436/617784
Title:
Characterisation of genetic and epigenetic aberrations in paediatric high grade glioma
Authors:
Channathodiyil, Prasanna
Abstract:
Paediatric high grade glioma (HGG), including diffuse intrinsic pontine glioma (DIPG) are highly aggressive tumours with no effective cures. Lack of understanding of the molecular biology of these tumours, in part due to lack of well-characterised pre-clinical models, is a great challenge in the development of novel therapies. Analysis of paired cell culture/biopsy samples in this study revealed that paediatric HGG short-term cell cultures retain many of the tumour characteristics in vivo. Using a genome-wide approach, copy number, gene and miRNA expression, and methylation changes were characterised in 17 paediatric HGG-derived short-term cell cultures including 3 from DIPG. The majority of the genomic changes were unique from those arising in adult HGG. Approximately 65% (11/17) of paediatric HGG short-term cell cultures had balanced genetic profiles resembling normal karyotypes. The most frequent copy number gain and loss were detected at 14q11.2 (94%) and 8p11.23-p11.22 (59%), respectively. H3F3A (K27M) mutation was present in 2/17 (12%) cases and concurrent loss of CDKN2A and BRAFV600E in 1/17 (6%) case. Genes involved in reelin/PI3K signaling (DAB1), RTK signaling (PTPRE), and arginine biosynthesis (ASS1 and ASL) were frequently deregulated by methylation in these tumours. The anti-growth and anti-migratory properties of DAB1 and PTPRE were demonstrated in vitro. Preliminary investigations validated the therapeutic potential of ADI-PEG20 (arginine depletion), and PI-103 (PI3K/mTOR inhibition) in a subset of paediatric HGG short-term cell cultures. This study has identified novel genetic and epigenetic changes in paediatric HGG that may, following further validation, be translated into potential biomarkers and/or therapeutic targets.
Issue Date:
2016
URI:
http://hdl.handle.net/2436/617784
Type:
Thesis
Language:
en
Description:
A thesis submitted in fulfilment of the requirements of the University of Wolverhampton for the degree of Doctor of Philosophy.
Appears in Collections:
E-Theses

Full metadata record

DC FieldValue Language
dc.contributor.authorChannathodiyil, Prasannaen
dc.date.accessioned2016-08-01T09:07:33Z-
dc.date.available2016-08-01T09:07:33Z-
dc.date.issued2016-
dc.identifier.urihttp://hdl.handle.net/2436/617784-
dc.descriptionA thesis submitted in fulfilment of the requirements of the University of Wolverhampton for the degree of Doctor of Philosophy.en
dc.description.abstractPaediatric high grade glioma (HGG), including diffuse intrinsic pontine glioma (DIPG) are highly aggressive tumours with no effective cures. Lack of understanding of the molecular biology of these tumours, in part due to lack of well-characterised pre-clinical models, is a great challenge in the development of novel therapies. Analysis of paired cell culture/biopsy samples in this study revealed that paediatric HGG short-term cell cultures retain many of the tumour characteristics in vivo. Using a genome-wide approach, copy number, gene and miRNA expression, and methylation changes were characterised in 17 paediatric HGG-derived short-term cell cultures including 3 from DIPG. The majority of the genomic changes were unique from those arising in adult HGG. Approximately 65% (11/17) of paediatric HGG short-term cell cultures had balanced genetic profiles resembling normal karyotypes. The most frequent copy number gain and loss were detected at 14q11.2 (94%) and 8p11.23-p11.22 (59%), respectively. H3F3A (K27M) mutation was present in 2/17 (12%) cases and concurrent loss of CDKN2A and BRAFV600E in 1/17 (6%) case. Genes involved in reelin/PI3K signaling (DAB1), RTK signaling (PTPRE), and arginine biosynthesis (ASS1 and ASL) were frequently deregulated by methylation in these tumours. The anti-growth and anti-migratory properties of DAB1 and PTPRE were demonstrated in vitro. Preliminary investigations validated the therapeutic potential of ADI-PEG20 (arginine depletion), and PI-103 (PI3K/mTOR inhibition) in a subset of paediatric HGG short-term cell cultures. This study has identified novel genetic and epigenetic changes in paediatric HGG that may, following further validation, be translated into potential biomarkers and/or therapeutic targets.en
dc.language.isoenen
dc.subjectpaediatricen
dc.subjectHGGen
dc.subjectDIPGen
dc.subjectgeneticen
dc.subjectepigeneticen
dc.subjectaCGHen
dc.subjectmiRNAen
dc.subjectmethylationen
dc.subjectPI3Ken
dc.subjectADI-PEG20en
dc.titleCharacterisation of genetic and epigenetic aberrations in paediatric high grade gliomaen
dc.typeThesisen
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