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Molecular genetic characterizations of human non-small cell lung cancer

by Tai, Lai-shan

Abstract (Summary)
(Uncorrected OCR) Abstract of thesis entitled Molecular genetic characterizations of human Non-Small Cell Lung Cancer Submitted by TAI Lai-Shan For the degree of Doctor of Philosophy at the University of Hong Kong in April 2005 Lung cancer is one of the most common malignances worldwide. It is the first leading cause of cancer death in both men and women in Hong Kong and in the United States. The prognosis of this prevalent disease is poor with a 5-year survival rate at about 15%. A better understanding of the underlying genetic molecular mechanism is crucial and essential for better diagnosis and therapeutic design purposes for cancer treatment. However, a clear molecular machinery for the carcinogenesis remains far to be discovered. In this study, genetic alterations of non-small cell lung cancer, the major subtype of human lung cancer were extensively studied. By using comparative genomic hybridization, the most frequent chromosomal regions showing DNA copy number gains and losses were investigated. Besides, patterns of chromosomal aberrations between adenocarcinoma and squamous cell carcinoma of NSCLC were compared and found to be greatly different. Results indicated that chromosome 3q gain is the most prominent difference between the two sub-groups (p<0.001). A candidate oncogene, eif-5A2, at chromosomal region 3q26, was found to be highly amplified in SCC, which suggests its role in tumorgenesis of SCC of lung. Association between genetic alterations and clinical significance was also investigated. Interestingly, we found that gains of chromosomes 5p and 20q and loss of 5q were significantly correlated to the advanced stage of NSCLC (p<0.05). More importantly, amplification of 1q was found to be correlated with tumor recurrence (p<0.05). All these observations suggest that chromosome 1q, 20q and whole chromosome 5 may harbor genes associated with tumor progression of NSCLC. We have established three human primary NSCLC cell lines and performed cytogenetic and molecular characterization of each. All of the three cells exhibited complex numerical and structural chromosomal changes. EGFR and FGF3 were found to be highly amplified and expressed in one of the NSCLC cell line. By studying protein expression in large sample population profile, we were the first to report the expression of FGF3 in NSCLC. Here we demonstrated the use of in vitro cell model for cancer-related genes identification and provide tools for further mechanistic and functional study. Apart from chromosomal gains, regions with DNA loss are also the study targets in tumorgenesis investigation. According to our CGH results, chromosome 3p is the region found with the most frequent copy number loss. Here we reported the use of SNP markers for high resolution 3p allelic loss study using Sequenom platform. Our data serve the basis for putative tumor suppressor genes identification in the future. An abstract of 412 words
Bibliographical Information:

Advisor:

School:The University of Hong Kong

School Location:China - Hong Kong SAR

Source Type:Master's Thesis

Keywords:lungs cancer genetic aspects molecular genetics

ISBN:

Date of Publication:01/01/2005

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