- Title
- Clinical use of SNP-microarrays for the detection of genome-wide changes in haematological malignancies with a focus on B-cell neoplasms
- Creator
- Berry, Nadine Kaye
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2020
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Haematological malignancies are a heterogenous group of cancers that originate in the mature or immature cells of the haemopoietic system. Some originate in the bone marrow, where stem cells differentiate into many types of immature blood cells, while others may form in the peripheral blood once the blood cell has matured. Each type of haematological malignancy is usually characterised by a distinct set of genomic changes that, when identified, can be used to make a specific diagnosis, predict response to therapy, provide a risk for relapse or chance of survival, characterise the disease further or provide a therapeutic target. These genomic changes are often well defined and recurrent in each type of haematological malignancy. Recent advances in technologies have also enabled the rapid discovery of novel findings – some of which have not been detectable by current standard clinical investigations performed at diagnosis. There are several techniques used to investigate the genome of haematological malignancies including G-banded karyotype, fluorescent in situ hybridisation (FISH) and various sequencing technologies. Currently, the primary technique used for the clinical genomic investigation of haematological malignancies is the G-banded karyotype, whereby analysis of banding patterns on chromosomes, which are visible in the metaphase of a cell cycle, is performed using a light microscope. This method of analysis has been the cornerstone of haematological malignancy characterisation since the discovery of the Philadelphia (‘Ph’) chromosome in 1960. However, there are many known limitations of this technique with low resolution and the need for dividing malignant cells being the most obvious. New cytogenomic tools, such as comparative genomic hybridisation microarray (CGH-microarray) and single nucleotide polymorphism microarray (SNP-microarray), overcome both the limitation of low resolution and the need for dividing cells by enabling the investigation of the whole genome at high resolution using DNA. However, the uptake of these techniques into clinical practice has been slow for haematological malignancy investigations. In this research endeavour, I sought to evaluate the clinical use of microarray technology for the investigation of haematological malignancies by assessing the performance of both CGH and SNP microarrays in comparison to current techniques. I focused on the platform’s ability to detect genomic changes that are known to hold prognostic value, as well as their ability to improve the detection of novel changes and those which are not detectable by current methodologies. In the first part of this research project I undertook a detailed literature review. Subsequently, I investigated the clinical use of CGH-microarrays for the detection of copy number variants (CNV’s) in haematological malignancies. The findings were compared to those observed using the current standard clinical investigations followed by a discussion of its prognostic implications. In the next step I used SNP-microarrays to further characterise the CGH-microarray findings. I evaluated the SNP-microarray for the identification and classification of prognostically important complex genomic signatures, such as chromothripsis and chromoanasynthesis, which are not identifiable by current clinical investigative tools. Finally, the impact of the detection of new prognostically important CNV’s identified at diagnosis by SNP-microarray were explored in a specific disease cohort. The literature clearly supports the use of new genomic profiling techniques that are only now beginning to transition from the research setting into clinical practice. Experts in the field of haematological malignancies recognise the role of genomic profiling as important for the understanding of this disease subset. However, research is still required to determine how significant the findings are and how to personalise treatment for patients based on these findings. It is imperative that the clinical diagnostic and treatment regimens do not fall too far behind advances made in research, particularly when it can have an immediate and positive effect on the patient.
- Subject
- genetics; SNP-microarray; haematological malignancy; thesis by publication
- Identifier
- http://hdl.handle.net/1959.13/1412536
- Identifier
- uon:36496
- Rights
- Copyright 2020 Nadine Kaye Berry
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 11 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 183 KB | Adobe Acrobat PDF | View Details Download |