Studies at a Molecular Level of the Association Between Human Papillomavirus DNA and Human Genital Carcinoma

Murdoch, John Bannatyne (1989) Studies at a Molecular Level of the Association Between Human Papillomavirus DNA and Human Genital Carcinoma. MD thesis, University of Glasgow.

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There is now considerable evidence for a close association between human papillomavirus (HPV) infection and genital neoplasia. These data are based upon epidemiological, colposcopic, cytological, histological, immunohistochemical and DNA hybridization studies. This thesis aims to study six aspects of this association. The first approach was to establish the prevalence of HPV 6, 11, 16 and 18 DNA sequences in human female genital premalignancy and malignancy in the West of Scotland. Three tissue sources were used; namely biopsies from abnormal tissue (vulval and cervical premalignant and malignant tissue), internal control tissues from histologically normal adjacent tissue and external control tissue from the cervices of cytologically normal women. HPV 6/11 DNA sequences were detected in only one premalignant lesion on the cervix (1.5%) and two external control tissues (6.7%). HPV 16 & 18 DNA was detected in 69% of cervical premalignant lesions, 80% of vulval premalignant lesions, 58% of cervical carcinomas and 60% of vulval carcinomas. HPV 16 was also detected in 2 external control tissues (6.7%). The prevalence of HPV 16 and 18 DNA is comparable with other studies but the prevalence of HPV 6/11 DNA is low suggesting a geographic variation in the prevalence of HPV DNA subtypes. This study confirms that HPV 16 is the subtype most frequently detected in these lesions (51% overall). HPV 16 DNA is however frequently detected in histologically normal tissue adjacent to neoplastic lesions (38.5% overall). Alternatively, HPV 18 DNA is less often detected than HPV 16 DNA (19% overall) but is more specific to histologically abnormal tissue [only one internal control biopsy hybridized to HPV 18 DNA, (1.5%)]. The second aspect of the association between HPV infection and genital neoplasia studied was the relationship between the different diagnostic methods used to determine the presence of HPV DNA on the cervix i.e. colposcopy, cytology, histology and immunohistochemistry. The sensitivity and specificity of Southern blot hybridisation allows this to be used as a "gold standard" for comparison with these other methods. The study showed that colposcopy was an insensitive method of identifying tissues which harboured HPV DNA as was immunohistochemistry. Cytology and histology suffered from a lack of specificity. These findings have implications for the assessment of patients and the structure of prospective study of the natural history of HPV infection which are discussed fully later. An association between HPV infection and advancing age has been suggested. In this thesis, no association between the age of patients and the detection of HPV DNA sequences was established. The high prevalence of HPV DNA subtypes in cervical neoplasia and the increasing data from cell line and cancer cell studies which suggest a mechanism for cell transformation by HPV DNA sequences has led to calls for the introduction of a screening test for HPV DNA. One such test utilizes dot blot hybridization. This study has compared Southern blot hybridization and slot (dot) blot hybridization. Slot blot hybridization has been shown to offer poor specificity, especially at low viral DNA copy numbers. Furthermore, this thesis shows that one third of patients who undergo laser ablation of the cervical transformation zone demonstrate persistence of the HPV genome following treatment. These two data, along with the facts that up to one third of the female population may harbour HPV DNA on their cervices, the prevalence of HPV DNA on the male penis is unknown, and a causal relationship between HPV DNA has not been established, suggest that screening for HPV DNA is not indicated at present in this country. The fifth aspect of the association between HPV DNA infection and cervical neoplasia to be studied was the influence of local irranunosurveillance as assessed by the presence of Langerhans' cells on cervical premalignancy. An association between HPV 18 DNA and HPV 16 DNA at high copy numbers and local immunosuppression was identified. It seems likely that smoking is associated with depression of Langerhans' cell activity and this study has demonstrated a possible relationship between these two epidemiologically important cofactors. Finally, a possible mechanism of cell transformation by HPV DNA comprises the amplification or upregulation of cellular oncogenes. In this thesis hybridization to the proto-oncogene c-myc was studied but no evidence of amplification of that oncogene was detected in association with hybridization to HPV DNA sequences. In two cases, however, there was some evidence to tentatively suggest a rearrangement of the c-myc oncogene in association with HPV 16 DNA detection. This aspect requires further study. The significance and implications of the results are discussed in the context of the work itself and its relation to the data reported by other workers. The implications for patient management are outlined and ideas for future work based on a tentative hypothesis are presented.

Item Type: Thesis (MD)
Qualification Level: Doctoral
Keywords: Medicine, Molecular biology
Date of Award: 1989
Depositing User: Enlighten Team
Unique ID: glathesis:1989-77851
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 14 Jan 2020 11:53
Last Modified: 14 Jan 2020 11:53

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