Investigation of the Aetiology of Hodgkin's Disease

Oncology

Gallagher, Alice

University:University of Glasgow

关键词: Oncology;   

Others  :  http://theses.gla.ac.uk/76310/1/13834043.pdf

来源: University of Glasgow

【 摘 要 】

Hodgkin's disease (HD) is a malignant lymphoma characterised by the presence of the Reed Sternberg (RS) cell, the proposed malignant cell of the disease, in a polymorphous cellular background. The aetiology of HD is unknown and is the subject of this thesis. The RS cells account for around 1% of the tumour mass and therefore characterisation of the RS cell has proven difficult. Epstein-Barr virus (EBV) has been detected in and localised to the RS cells in around 40% of HD tumours. The EBV latent membrane protein 1 (LMP-1) is expressed by the RS cells in EBV- positive cases. LMP-1 has been shown to up-regulate the B-cell lymphoma-2 [bcl-2] proto-oncogene and increased Bcl-2 expression is known to protect cells from apoptosis or programmed cell death. In addition the t(14;18) translocation, which also causes increased Bcl-2 expression, had been reported previously in HD. We investigated a series of HD cases for the presence of the t(14;18) translocation utilising a PCR technique. In a proportion of cases a comparison between LMP-1 and Bcl-2 expression was made. We found few translocations present in the HD cases examined and in addition no correlation was observed between LMP-1 positivity and Bcl-2 expression. We conclude that the t(14;18) translocation is an infrequent finding in HD and is unlikely to play an aetiological role in this malignancy. An animal model for the study of HD would aid in studies such as that described above. The use of severe combined immunodeficient (SCID) mice for the study of human malignancies has been well documented. We attempted to engraft HD-derived tumour tissue into SCID mice in order to propagate RS cells for the subsequent investigation of viral and oncogene involvement in this disease. In addition tumour cell suspensions from non-Hodgkin's lymphoma (NHL) samples were also transplanted into SCID mice. The transplantation of NHL tumour cell suspensions was a success, with a proportion of tumours in SCID mice showing identical genotype and phenotype to original biopsy material. The transplantation of HD tumour material into the SCID model was however less successful with SCID tumours showing an EBV-driven lymphoproHferative phenotype indicating that outgrowth of EBV-infected bystander cells in the tumour had occurred. At present the SCID model appears an unsuitable system for the propagation of the RS cells of HD. HD has a bimodal age incidence curve with a peak incidence in young adults; the cases within this peak particularly those of the nodular sclerosis subtype are infrequently EBV-associated. Epidemiological studies suggest that an infectious agent may be involved in the aetiology of the young adult disease. Candidate infectious agents are herpesviruses since they are widespread in nature and establish persistent infection. We devised a PCR strategy for the detection of herpesvirus sequences in DNA samples using primers based on two well- conserved regions of the herpesvirus glycoprotein B gene. The assay has sufficient sensitivity to detect herpesvirus sequences if present within the RS cells of a HD biopsy specimen. The assay also has the capability of distinguishing between different herpesviruses within a given sample. Use of a technique such as this may show that another herpesvirus is involved in the pathogenesis of the non EBV-associated cases of HD.