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This dissertation, Allelic and Molecular Changes in Multistep Process of Hepatocarcinogenesis by Oi-lin, Irene, Ng, 呂愛蓮, 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 Allelic and Molecular Changes in Multistep Process of Hepatocarcinogenesis Submitted by Irene Oi-lin NG For the degree of Doctor of Philosophy at the University of Hong Kong in September 2005 Hepatocellular carcinoma (HCC) is one of the commonest malignancies worldwide and also in Southeast Asia and Hong Kong. Similar to other cancers, hepatocarcinogenesis is of a multistep process. However, systematic analysis using a genetic or molecular approach to accurately delineate the different steps/stages of HCC development is scarce. The aim of this study was to systematically evaluate the allelic alterations in the multi- steps in hepatocarcinogenesis including chronic hepatitis/cirrhosis, dysplastic nodules, primary and metastatic HCCs. In order to delineate tumor progression pathologically, a large cohort of 655 patients with resected primary HCC was studied. Tumor progression, as reflected by growth of tumor size, was associated with a more aggressive behavior with more frequent venous invasion and tumor microsatellite formation, and advanced tumor stage. To delineate the frequency of allelic losses in chronic hepatitis and cirrhosis, genome- wide allelotyping was performed, by comparing them with the corresponding normal DNA. Loss of heterozygosity (LOH) in cirrhotic/chronic hepatitis livers was uncommon, with overall fractional allelic loss (FAL) index of 0.005. In contrast, LOH was a common occurrence in the corresponding predominantly hepatitis B virus (HBV)-associated HCCs, with 70.6% exhibiting LOH at >=1 loci and an overall FAL index of 0.169 0.002. The development of dysplastic nodule (DN) has been the subject of study with regard to its role in hepatocarcinogenesis. All the 17 DNs from 13 patients who underwent either surgical resection or liver transplantation showed LOH at one or more loci on the chromosomes tested. Importantly, the FAL of the high-grade DNs (0.34 0.20) was significantly higher than that of the low-grade DNs (0.16 0.07) and was close to that of HCC, showing that high-grade DNs are genetically and thus behavior-wise close to HCC. The FAL index was determined in 74 HCC nodules (mean S.D., 0.39 0.23). The molecular relationship between multiple tumor nodules (n = 25) in HCC within individual patients (n = 11) was also determined with both LOH assay and comparative genomic hybridization (CGH). The results indicated that in 36% of patients, the multiple HCCs had different clonalities, hence of multicentric origin, whereas in the remaining 64% patients, the multiple HCCs had similar clonal relationship, hence of intrahepatic metastasis (IM). Assessment of DNA alterations allowed precise determination of the clonality of multiple HCCs within one patient. Also, a cut-off value of 30% of discrepancy of LOH patterns between the nodules was found to distinguish IM and multicentric occurrence. Consistently, those multinodular HCCs with Overall, hepatocarci

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