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Identification of putative tumor suppressor gene activities in nasopharyngeal carcinoma

Authors Cheng, Yue
Issue Date 2002
Summary Nasopharyngeal carcinoma (NPC) is a cancer that is rare in most areas of the world, but is particularly prevalent in southern China, including Hong Kong. As yet, very little is known about the molecular genetic changes involved in NPC. Previous findings from cytogenetic and molecular allelotyping approaches implicate several chromosomes as harboring possible tumor suppressor genes (TSGs) of importance for NPC development. To isolate the gene(s), it is necessary to map the location of TSGs more precisely and to distinguish a critical region from extensive randomly lost areas. Since deletion studies provide only indirect evidence for the tumor suppressive activities in NPC, it is necessary to obtain functional evidence for tumor suppression before laborious candidate gene cloning attempts are made. The technique of monochromosome transfer as a functional assay for TSG activity is particularly useful in confirming TSG functions associated with specific chromosomes, where the map location is suspected but no candidate TSG has yet been cloned. The transfers of selected chromosomes into an NPC cell line, HONEl, were performed to determine whether tumor suppressing activities for NPC mapped to chromosomes 3, 9, 11, 13, 14 and 17. The studies showed tumor suppressive activities mapping to chromosome 3, which were later regionalized to 3p21.3 by using four truncated chromosome 3 fragments for transfer. No functional suppression of tumor development in nude mice was observed with microcell hybrids harboring the transferred chromosome 9 containing a microdeletion at 9p21, where a known TSG, p16, maps. However, transfection of p16 into the HONE1 cells resulted in obvious growth suppression and provided strong functional proof of the involvement of p16 in NPC. The tumorigenicity of the HONE1 cell line was also suppressed by an extra intact copy of chromosome 11 in all hybrids. Further molecular analysis of chromosome 11 tumor segregants indicated that at least two tumor suppressive regions were involved at the 11q13 and 11q22-23 areas. Using molecular approaches and fluorescent in situ hybridization, this study has narrowed down the critical region at 11q13 to a 1.8 Mb interval. The introduction of an intact of chromosome 17, which contains a copy of the wild type p53 TSG, could not reverse the tumorigenic phenotype of HONE1 cells, which carry a heterozygous point mutation at codon 280. The results suggest that the heterozygous mutation of p53 is not essential for tumorigenesis of HONE1 cells. Results of these studies also suggest the presence of other candidate tumor suppressor genes on the chromosomes 13q12-14, 14q12 and 14q32.1 by analysis of HONE1/chromosome 13 and 14 hybrids. These studies, based on the functional genomic investigations, suggest that multiple TSGs contribute to the development of NPC and conclude that a multiplicity of genetic alterations at 3p21.3, 9p21, 11q13, 11q22-23, 13q12-14, 14q12 and 14q32.1 is important in NPC development.
Note Thesis (Ph.D.)--Hong Kong University of Science and Technology, 2002
Language English
Format Thesis
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