Studies into the Role of Herpes Simplex Virus and Human Papillomavirus in Cervical and Vulval Cancer

Walkinshaw, Stephen Andrew (1990) Studies into the Role of Herpes Simplex Virus and Human Papillomavirus in Cervical and Vulval Cancer. MD thesis, University of Glasgow.

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DNA extracted from tumour biopsies obtained from 14 women undergoing radical surgery for cervical cancer, from 10 women undergoing surgery for vulval cancer and from internally matched control tissue from the myometrium in 8 cases of cervical cancer and from abdominal skin in 2 cases of vulval cancer was examined for the presence of HSV-2, HPV-6, 11, 16 and 18 DNA using Southern blot transfer and DNA-DNA hybridisation. Sequences homologous with the MTRII region of herpes simplex virus type 2 were detected in one of nine invasive cervical cancers and in one of ten invasive vulval cancers. No tumour or normal tissue showed evidence of hybridisation to HPV-6 or 11 DNA and HPV-18 DNA was detected in only 2 of 22 tumours tested. HPV-16 DNA was detected in 10 of 14 cervical tumours and in 8 of 10 vulval tumours. The copy number and integration patterns in individual tumours varied widely. HPV-16 DNA was also detected in 7 of 10 internally matched control tissue biopsies. In one case the integration pattern differed between tumour and control tissue. Long term follow up of patients demonstrated no prognostic significance in the presence or absence of viral DNA in either tumour or normal tissue. These studies did not support a definitive role for HPV-16 in either cervical or vulval cancer. To determine the function of viral DNA in these cancers, attempts were made using these and 14 other tumours to derive new continuous cell lines by a primary explant technique. These cell lines, where the state of viral DNA in the original tumour and in internally matched normal control tissue would be available, could be valuable model systems for examination of cell-viral interaction. Two continuous cervical cell lines, designated Tu 22-1 and Tu 22-2 were derived from a biopsy of a squamous cancer. These cell lines differed in their requirement for epidermal growth factor, their ability for anchorage independent growth, their production of B-HCG and in their cytogenetic characteristics although they were morphologically indistinguishable. Both cell lines contained detectable HPV-16 DM in a similar complex pattern. The original tumour also contained HPV-16 DM but internally matched control tissue for this tumour did not contain such DNA. One new cell line, Tu 31, was derived from a squamous cancer of the vulva following passage through an athymic mouse. This cell line fulfilled the requirements of an established human cell line. Single insert HPV-16 DM was detectable in this line. The original tumour biopsy also contained HPV-16 DM but in a complex configuration. Low copy single insert HPV-16 DM was present in internally matched normal tissue from this patient. As it was clear from the DM studies that the presence of viral DM alone was not sufficient to explain malignant change, complementary clinical studies of pre-invasive cervical cancer were undertaken to establish which other factors might be involved. A cross-sectional study of 200 women with cervical intra-epithelial neoplasia (CIN), 36 women with cervical HPV infection and 100 normal control women from the same geographical area as the DM study, demonstrated a relative risk for CIN of 2.0 for ever use of oral contraceptives and 2.57 for cigarette smoking with a trend towards a dosage effect and a possible relationship between number of cigarettes smoked and severity of histological change. Previous exposure to human cytomegalovirus imparted a small risk (1.57) for CIN in this population. A smaller prospective study of women presenting with overt genital warts confirmed that smoking was associated with an increased risk of histological cervical abnormality but contained insufficient numbers to determine if any one factor was associated with progression following exposure to HPV infection. These studies urge caution in the assumption that HPV infection plays a major role in lower genital tract cancer and emphasise that other factors may be as important. Aetiological factors implicated in cervical and vulval cancer are reviewed and the evidence for a role for HPV critically assessed.

Item Type: Thesis (MD)
Qualification Level: Doctoral
Keywords: Medicine, Virology, Pathology
Date of Award: 1990
Depositing User: Enlighten Team
Unique ID: glathesis:1990-78178
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 28 Feb 2020 12:09
Last Modified: 28 Feb 2020 12:09

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