In the United States, ovarian cancer is the leading cause of death from gynecological malignancies and is the fifth most common female malignancy. In 2000, approximately 23,1000 women will be newly diagnosed and 14,000 will die from ovarian cancer. Unfortunately, the majority of patients are diagnosed with advanced with advanced disease. Five-year survival rates for these patients are poor. The dismal prognosis results from an inability to detect the tumor early when it is curable and from the lack of effective therapies for advanced disease. These facts motivate the present proposal to continue to explore molecular events that enable initiation or progression in sporadic ovarian cancer under the hypothesis that this information will enable earlier detection, improve prognostication and/or identify novel therapeutic targets.
Our specific aims are to: (1.A.) Apply array CGH and expression array analysis to detect and localized recurrent genome copy number or gene expression changes in low stage and grade tumors (100 tumors), in stage II + III (100 tumors) and in serous, endometroid, mucinous, clear cell and borderline tumors (50 tumors each) plus selected cell lines. (1.B) Establish associations between genome copy number and/or expression changes in histology, progression and/or clinical outcome. These associations will be validated by analysis of tissue microarrays. (2.A) Precisely define regions of recurrent genomic change using high-resolution array CGH. Initial emphasis will be on regions of increased copy number at 3q, 8p, 20q and a region of loss at 16q. These regions have been associated with poor clinical outcome in chromosome CGH analyses or appear to be early events in the development of ovarian cancer. (2.B) Identify genes associated with narrowly defined regions by comparative (mouse vs. human) genomic sequencing and analyze these for expression level in a large number of tumors using tissue microarrays. (2.C) Assess genes implicated in ovarian cancer progression for mutations, functional polymorphisms and for their ability to modulate transformation, gene expression, apoptosis, invasion and genomic instability in cultured ovarian cancer cell lines and ovarian surface epithelium (OSE).
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