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Title: Molecular characterisation of canine lymphoma
Author: Waugh, Elspeth Margaret
ISNI:       0000 0004 5348 0829
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2015
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Lymphoma is the most common haematopoietic malignancy of dogs, but little is known about its aetiology and pathogenesis. Canine lymphoma is composed of a clinically heterogeneous group of tumours, as in human non-Hodgkin lymphoma (hNHL), which shares many similarities with the canine disease. In humans, lymphoma is classified into many different subtypes, each with its own clinicopathological characteristics, prognosis, and in many cases, treatment regime. In dogs, diagnosis is often rudimentary, and many cases are not routinely or robustly subtyped. This has hampered efforts to develop accurate prognostic indicators and novel therapies, as heterogeneous groups of cases are analysed. More accurate classification of canine lymphomas is required before real progress can be made. In the work described in this thesis, molecular techniques were used to develop diagnostic tests to aid diagnosis of canine lymphoma, with a view to improving disease classification, and gaining a greater understanding of disease pathogenesis. The diagnosis of canine lymphoma can be assisted by PCR for antigen receptor rearrangements (PARR), which can determine clonality and tumour cell lineage. Diagnostic samples from suspected lymphoma patients were screened with multiple published PARR primers to establish a panel of assays for routine use. Primer coverage was assessed, and modifications to both primer sequences and primer combinations made where necessary. The optimised PARR assay was robust, highly sensitive and specific, comparable with published studies and provided useful diagnostic information unavailable from other tests. In humans, the Epstein-Barr virus (EBV) is associated with several lymphoma subtypes. Recently, it has been suggested that EBV or an EBV-like virus is circulating in dogs. Serological and molecular techniques were used to investigate whether EBV, or a novel herpesvirus, is associated with canine lymphoma. In an assay designed to detect antibodies to EBV viral capsid antigens, 41% of dogs were positive. Dogs with cancers, including lymphoma, were more frequently positive than controls, but no particular association with B-cell lymphoma was noted. EBV-specific RNA and DNA sequences were not detected in lymphoma tissue by in situ hybridisation or PCR and herpesvirus genomes were not detected using multiple degenerate PCR assays with the ability to detect novel herpesviruses. No evidence that herpesviruses are directly involved in common types of canine lymphoma was found, although the presence of an EBV-like virus in the canine population cannot be excluded. Gene expression profiling has been used to subtype human diffuse large B-cell lymphoma, and to provide insight into pathogenesis. Next-generation sequencing was used to generate transcriptome data from a panel of canine B- and T-cell lymphomas. Gene expression analysis showed clear clustering of B-cell and T-cell types, and suggested that differentiation within the B-cell group was possible. Pathway analysis demonstrated up-regulation of genes in pathways appropriate to the tumour type. Sequence data were also explored to identify variants in important genes and pathways which may have functional consequences. Many affected genes were identified, and comparison with hNHL suggested that common driver mutations are present. By identifying novel targets, such studies may pave the way for development of new therapies to benefit both man and dog.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: SF600 Veterinary Medicine