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Epigenetic analysis of childhood leukaemia and the Hippo pathway

Dunwell, Thomas Lawson (2010)
Ph.D. thesis, University of Birmingham.

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Abstract

Hypermethylation of CpG islands is one of the many processes that a developing cancer cell may use for the inactivation of tumour suppressor genes. The Sav/Hippo/Warts pathway was originally identified in Drosophila and shown to be responsible for controlling both growth and apoptosis, implying this is a tumour suppressor pathway. This pathway is both evolutionarily and functionally conserved in mammals. Work presented here shows that apart from FAT1 and YAP other pathway members are not epigenetically silenced in common epithelial or haematological cancers. FAT1 and YAP were frequently methylated in childhood acute lymphoblastic leukaemia (ALL) but unmethylated in epithelial cancers. Childhood ALL is a blood cancer with peak prevalence between the ages of 3-5 years. The epigenetics of this cancer were examined with three separate approaches; the first, a candidate gene approach, second a NotI restriction enzyme based array examining the methylation of genes residing on chromosome 3, and thirdly the methylated-CpG island recovery assay (MIRA) combined with CpG island arrays examining methylation on a genome-wide scale. These approaches identified a large number of novel genes which were frequently methylated in ALL. Many of the identified genes were new methylation targets and were shown to be likely targets for methylation in both common epithelial and haematological cancers. A series of these genes was seen to be specifically methylated in different leukaemia sub types, and to cluster T-ALL and B-ALL samples into high and low methylation clusters. When examined in chronic lymphoblastic leukaemia (CLL) methylation of two of the above genes was associated with disease progression and methylation of another gene was associated with response to clinical treatment.

Type of Work:Ph.D. thesis.
Supervisor(s):Latif, Faridi
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:School of Clinical and Experimental Medicine
Subjects:RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Institution:University of Birmingham
ID Code:991
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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