Characterization of Chromosome 3 anomalies and 3p genes implicated in human epithelial ovarian cancer

Cytogenetic, loss of heterozygosity (LOH) and midrocell-mediated chromosome transfer (MMCT) analyses of epithelial ovarian cancer (EOC) have provided evidence for the role of genes on the short arm of chromosome 3 (3p) in the development of this disease. LOH analysis of ovarian tumors performed in the laboratory of Dr. Tonin identified two minimal regions of deletion (MRD) at 3p25--p26 and 3p24, and a third region extending from 3p14 to the centromere. Based on this study, I hypothesized that there are at least three tumor suppressor genes (TSG)s on the 3p arm that function in suppressing ovarian tumorigenesis. In this thesis, I utilized the novel technology of expression microarrays to identify candidate TSGs based on differential patterns of expression in four well-characterized EOC cell lines compared to a primary culture derived from normal ovarian surface epithelium. MMCT of chromosome 3 into the EOC cell line, OV-90 that harbors complete LOH of one 3p arm resulted in strong suppression of growth. Rapid growth arrest was induced in OV-90 derived hybrids despite the presence of a somatic mutation in TP53 coincident with allele loss at the gene locus. These results suggest that at least one TSG on chromosome 3 is able to function independently of TP53, consistent with the observation made in this thesis that LOH of 3p loci is not significantly associated with somatic mutations in TP53. The acquisition of a growth rate similar to OV-90 in sub-populations of two of the hybrids generated was associated with four regions of deletion on the transferred chromosome 3 at 3p26-pter, 3p14--p21, 3p12--p13, and 3q26--q27, demonstrating the first functional evidence for a TSG important in EOC that maps to each of these regions. Extensive LOH analysis of the 3p25--p26 region of deletion previously identified allowed the definition of a new MRD at 3p26.3 that overlaps the 3p26-pter interval identified in the MMCT study. Expression analysis of genes t