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This dissertation, Dynamics of Chromosome Instability in Human Cells Undergoing Immortalization by Wen, Deng, 鄧文, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled Dynamics of chromosome instability in human cells undergoing immortalization submitted by Wen DENG for the degree of Doctor of Philosophy at The University of Hong Kong in March 2005 Chromosome instability is a major form of genomic instability observed in most human cancers. By continuous generation of new structural and numerical chromosome aberrations, it provides cells with selective advantages during cancer development. Since cellular immortalization is an early and indispensable step towards cancer, I explored the dynamics of chromosome instability during human cell immortalization to obtain a better understanding of mechanisms involved in the early process of carcinogenesis. It has been a long-standing mystery why pre-immortal, immortalized and cancer cells universally have nonrandom chromosome aberrations. Some hints, however, emerged from recent studies on telomeres, the terminal chromosomal structure crucial for maintaining genomic integrity. Telomere lengths on individual chromosomes have been found to be highly heterogeneous, leading to an exciting hypothesis that chromosomes with the shortest telomere may be most susceptible to structural instability. Testing this hypothesis requires quantification of individual telomere signals and analysis of chromosomal structural aberrations on optimally spread metaphases. Using newly developed methods for metaphase chromosome preparation and quantitative telomere 1fluorescence in situ hybridization (Q-FISH) combined with whole-chromosome painting, I demonstrated that chromosomes with the shortest telomeres were indeed most frequently involved in structural aberrations in pre-immortal human ovarian surface epithelial cells (HOSE 6-3). This cell line was established by expression of human papilloma viral oncogenes (HPV16 E6E7) which inactivate p53 and RB proteins. Since most human cancers have p53 and RB pathway defects, the cell system is relevant to cancer. Encouraged by the above finding, I further applied telomere Q-FISH and spectral karyotyping (SKY) to obtain whole-genome data in multiple cell lines derived from HOSE and esophageal epithelial cells expressing HPV16 E6E7. My results showed that cell lines derived from unrelated donors had distinct profiles of critically short telomeres, which were highly significantly associated with the different profiles of chromosomal structural aberrations. These findings demonstrated that distinct profiles of critically short telomeres in different human individuals played an essential role in determining the individual-specific chromosomal structural aberrations during cell immortalization. In addition, I observed that centromeric or pericentromeric regions were prone to breakage subsequent to telomere dysfunction-mediated end-to-end fusions, evidenced by the dynamic increases of centromeric aberrations with cell proliferation, especially on those chromosomes that originally had the shortest telomeres. Centromeric instability was also detected in cell lines immortalized by two other methods, i.e., human telomerase reverse transcriptase (hTERT) expression, or co-expression of HPV16 E6E7 and hTERT, albeit to lesser extents. These results revealed a general role of centromeric instability in 2shaping the outcomes of chromosome aberrations in human cells undergoing immortalization. Finally, persistent numerical chromosome instability, manifested as dynamic gains or losses of whol

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