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Title: Analysis of candidate tumour suppressor genes in sporadic ovarian tumours
Author: de Foy, K.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 1998
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The aim of this thesis was to identify genes which are important in the initiation and/or progression of sporadic ovarian cancer. A series of ovarian teratomas and carcinomas was collected and three candidate tumour suppressor genes were analysed. The c-mos gene is an ovarian teratoma susceptibility gene in mice; its absence causes the growth of these tumours. Twenty human ovarian teratomas were collected and the coding region of the c-mos gene was analysed for somatic and germline mutations. No disease-causing alterations were found. Germline mutations of the BRCA2 gene predispose individuals to breast and ovarian cancer. To determine whether mutations in BRCA2 are important in sporadic ovarian cancer, loss of heterozygosity studies and mutation analysis were carried out on BRCA2 in a series of sporadic epithelial ovarian tumours. Loss of heterozygosity was identified in 46% of tumours. Four truncating mutations were identified in 50 tumours, two of which were germline and two somatic. All four mutations were accompanied by loss of the second allele. These results suggest that BRCA2 behaves as a tumour suppressor gene but that somatic mutations are not a common even in sporadic ovarian cancer. The insulin-like growth factor II receptor gene (IGF2R) on chromosome 6q is in a region which is frequently lost in ovarian tumours. A loss of heterozygosity analysis of the IGF2R locus in 38 informative epithelial ovarian tumours demonstrated 55% with loss of one allele. To perform mutation analysis of IGF2R, the technique of fluorescent chemical cleavage of mismatch was established in the laboratory and used to analyse IGF2R cDNA from 18 tumours. No disease-causing alterations were identified. Antibodies were used to examine the expression of the IGF2R protein through immunohistochemical studies of 53 ovarian tumour tissue sections. Seven tumours were identified in which epithelial tumour cells stained negatively for IGF2R. No correlation could be found between immunohistochemical results and LOH and mutation analysis results, suggesting that IGF2R is probably down-regulated at the level of transcription or translation in those samples which showed negative staining.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available