Alameri, Mohamed;
(2023)
Epigenetic profiling for minimal residual disease in paediatric acute myeloid leukaemia.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Studying epigenetic markers in cancer has been changing the way we understand and treat this disease. Paediatric acute myeloid leukaemia (AML) is a heterogeneous disease and one of the most challenging cancers to treat. Recent studies have shown that there are improvements in the therapies. However, even after treatment, children have around a 40% chance of relapse, making it one of the highest relapse rates among all cancer types in paediatrics (Im, 2018b). This study aims to find specific epigenetic markers that allow us to follow minimal residual disease (MRD) in AML to predict the relapse rate. Analysis of 147 samples from AML TARGET database and 30 primary samples from Great Ormond Street Hospital (GOSH) using microarray with the addition of machine learning algorithms identified eight best-fit DNA methylation markers that can discriminate between presentation/relapse and remission normal samples. Validation of the best-fit markers using qPCR with methylation-sensitive SYBR green primers resulted in low specificity in leukaemia versus normal samples. This led us to target methylation sequencing to identify novel CpGs adjacent to the best-fit markers with lower methylation values. TaqMan primer/probes sets were designed to validate the new CpGs. Due to the difficulty in designing effective TaqMan assays targeting the CpG, this approach was only partially successful. Therefore, targeted methylation sequencing using leukaemia-spiked normal samples mimicking MRD environment was performed. However, this approach suffered from a lack of sensitivity. Nevertheless, this study identified areas of DNA hypermethylation that can discriminate between AML and normal/remission samples and may serve as a starting point for the development of a novel diagnostic assay for MRD in paediatric AML.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Epigenetic profiling for minimal residual disease in paediatric acute myeloid leukaemia |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10163850 |
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