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Title: Molecular and cell genetic analysis of chromosome 11 in sporadic epithelial ovarian cancer
Author: Gabra, Hani
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1997
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I used PCR based polymorphic microsatellites to define frequent loss of heterozygosity (LOH) at 11p15.5-15.1 and 11q23-qter in DNA blood/tumour pairs from 60 patients with ovarian neoplasms. LOH at 11q23-qter was significantly associated with advantaged stage and adverse actuarial survival. Integration of this LOH data allowed construction of a multistep model for ovarian cancer. Refinement of the 11q23-qter region revealed an 8.5Mb LOH region between D11S934 and D11S1320 (11q23.3-q24.3) retaining the above survival association. To test the causality of the LOH observations, I introduced normal chr 11 by microcell mediated chromosome transfer (MMCT) into an ovarian cancer cell line. I used 556.1.5, a human monochromosome somatic cell hybrid to transfer neor-tagged chr 11 into Hygr subline of OVCAR3 (OH3), an ovarian cancer line with a chr 11 rearrangement. I have analysed 14 microcell hybrid clones (MHCs) from 5 experiments. Chr 11 transfer was confirmed by PCR, in situ hybridisation and microsatellite analysis. Interestingly, chr 12 MMCT, originally intended as a negative control was shown to inhibit the growth of OH3, suggesting the presence of a TSG on this chromosome. Chr11 MHCs remained immortalised, and demonstrated significant in vitro growth inhibition. This inhibition was not due to cell cycle block (DNA FACS analysis) or apoptosis (FITC-labelled Annexin-V and fluoro-TUNEL FACS analysis). MHCs were significantly reduced in their ability to invade matrigel in the transwell invasion assay. MHCs retaining whole chr 11 showed significant reduction in invasiveness compared with MHCs taking up all chr 11 as far as 11q22. Soft agar clonogenicity was unaltered. Xenographs of chr 11 MHCs showed growth delay rather than suppression of tumorigenicity. These studies suggest that the gene(s) on chromosome 11 functions as an ovarian cancer progression-suppressor and provides a starting point for an integrated positional/functional cloning approach.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available