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This dissertation, Molecular Analysis of Mitochondrial DNA Alterations in Endometrial Carcinomas by Yue, Wang, 王悦, 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 Molecular Analysis of Mitochondrial DNA Alterations in Endometrial Carcinomas Submitted by Wang Yue for the degree of Doctor of Philosophy at The University of Hong Kong in June 2005 Recently, mitochondrial DNA (mtDNA) mutations and genetic instability were frequently detected in a number of human cancers. However, the occurrence of mtDNA alterations in endometrial carcinomas is still unknown. This study aims to identify the frequency and characteristics of mtDNA alterations in endometrial carcinomas. To identify somatic mtDNA mutations, DNA sequencing was performed on the mutational hotspot region of mtDNA in endometrial carcinomas and matched normal controls. The frequency of the T→C polymorphism at nucleotide position (np) 16189 was also determined in endometrial carcinomas and compared with the frequencies detected in cervical, ovarian and breast cancers as well as in the general population. The mitochondrial microsatellite instability (mtMSI) in the above four types of cancers was also evaluated. The nuclear MSI (nMSI), the germline mutations of the core genes of the mismatch repair system and methylation status of hMLH1, APC INK4A and p16, were also studied in endometrial carcinomas. 1The copy number of mtDNA in endometrial cancer cells procured by laser capture microdissection (LCM) was determined by real-time quantitative PCR and compared with normal endometrial cells obtained from the same patient. Moreover, by using LCM, mtDNA sequence alterations were analyzed on different loci from the same lesion of a subset of endometrial carcinomas. Finally, the mtDNA copy number and the expression level of mtDNA-encoded genes on estrogen-sensitive RL95-2 cells were quantified by real time PCR, RT-PCR and Western blotting assays. A remarkably high frequency (56%, 28/50) of somatic mtDNA mutations in endometrial carcinomas was observed. MtMSI constituted the majority (89%, 25/28) of the somatic changes detected. And the frequency of mtMSI was significantly higher than the other three types of cancers including cervical, ovarian and breast cancers (χ, P

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