Common amplicons were delineated throughout the NPC genome in a large panel of NPC cell lines, xenografts, and primary tumors by two high-density genomic arrays with ∼1 Mb and 35 kb resolution. Apart from the genetic changes reported in previous studies, a number of novel chromosomal aberrations were discovered, including gains at 7p11, 16p13.3, 19p13, 19q13-q43 and 20q13. Most distinctively, common amplicons at 11q13 and 12p13 were found in this cancer. Two smallest amplification regions with 5.4 Mb and 2.16 Mb were delineated at 11q13.1-q13.3 and 12p13.31 respectively. The high prevalence of these 2 amplified regions have led to the hypothesis that activation of the target oncogenes in these regions are critical events for NPC development. / Expression of candidate genes located within 11q13.3 was examined and consistent overexpression of CCND1 in cell lines and xenografts were identified in the 11q13.3. Frequent concordant gains and overexpression of CCND1 were further confirmed in primary tumors. Knockdown of CCND1 mRNA by siRNA technique was found to inhibit cell growth and lead to cell cycle arrest at G1. Alterations of protein expressions of other cell cycle components were also observed. Moreover, inactivation of p16 and overexpression of cyclin D1 were commonly occurred in NPC. These findings provided evidence that cyclin D1 may have cell cycle-independent functions, which is critical in NPC tumongenesis. / Frequent gains of 12p13.31 region were confirmed by fluorescence in situ hybridization (FISH) analysis. According to expression array and real-time RT-PCR results, LTbetaR, TNFRSF1A and FLJ10665 were the three genes showing concordant amplification and overexpression in NPC xenograft. The LTbetaR protein, which is a lymphotoxin beta receptor, was confirmed to be recurrently overexpressed in NPC primary tumors and its overexpression may be involved in the activation of NF-kappaB in NPC. The findings suggested that it is one of the candidate oncogenes of this cancer. / In summary, three candidate NPC-associated oncogenes locating at 3q26.32, 11q13.3 and 12p13.31 were identified by genome-wide mapping analysis. Molecular and functional characterizations of these genes have provided evidences that they play critical roles in NPC tumorigenesis. / In this study, detailed investigation was carried out on a candidate NPC-associated oncogene, PIK3CA at 38q26.32, an amplicon reported previously. Copy number gains and amplifications of this gene, but not mutation, were demonstrated to be common events in NPC. The findings hence implied the importance of PIK3CA in NPC tumorigenesis. / Nasopharyngeal carcinoma is a common cancer in Southern China. Despite multiple genetic changes have been reported previously, limited information of NPC-associated oncogene is available. Since amplification is one of the major mechanisms in oncogene activation, a comprehensive characterization of common amplicons in human cancers is expected to facilitate the identification of the oncogenes involved in tumorigenesis. The aims of the present study is to define and characterize the common amplicons in NPC genome and then to identify NPC-associated oncogenes. / Or Yan Yan. / "July 2006." / Adviser: Kwok Wai Lo. / Source: Dissertation Abstracts International, Volume: 68-09, Section: B, page: 5715. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 179-201). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.
| Identifer | oai:union.ndltd.org:cuhk.edu.hk/oai:cuhk-dr:cuhk_343852 |
| Date | January 2006 |
| Contributors | Or, Yan Yan., Chinese University of Hong Kong Graduate School. Division of Anatomical & Cellular Pathology. |
| Source Sets | The Chinese University of Hong Kong |
| Language | English, Chinese |
| Detected Language | English |
| Type | Text, theses |
| Format | electronic resource, microform, microfiche, 1 online resource (xviii, 201 p. : ill.) |
| Rights | Use of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
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