Ovarian cancer is the fifth most common form of cancer in women in the United States, accounting for 4% of the total number of cancer cases and 25% of those cases occur in the female genital tract. Because of its low cure rate, it is responsible for 5% of all cancer deaths in women. It was estimated that 13,000 deaths was caused by ovarian cancer in the year 2001. A majority of ovarian cancer cases are detected at an advanced stage (where metastases are present beyond the ovaries) and are rarely curable. Although 80% of advanced ovarian cancers respond to primary treatment with surgery and chemotherapy, the disease usually recurs and is ultimately fatal. Though most patients die within 2 years of diagnosis, a subset of patients develop a more chronic form of ovarian cancer, and may survive 5 years or more with treatment. It is possible that patients with indolent cancer should be monitored and treated differently from patients with rapidly progressing ovarian cancer. At this point, clinicians do not have the tools to predict the clinical course of disease. The proposed studies seek to develop a molecular characterization for this purpose. We propose to apply the newly established cDNA array comparative genomic hybridization (CGH) technique to generate DNA copy number abnormality (CNA) profiles on ovarian cancer samples collected from patients entered into the Gynecologic Oncology Group (GOG) 9404 clinical trial, which has thorough information regarding patient outcome following primary cytoreductive surgery and platinum-based first-line chemotherapy. Using the cDNA array as a platform, we have identified cyclin E amplification and over-expression in a majority of ovarian tumor tissue. Furthermore, using the specimens from the GOG protocol 9404, we have demonstrated that cyclin E is a prognostic marker for ovarian cancer. Based on these promising preliminary data, we propose (1) to identify DNA copy number abnormalities in ovarian cancer by cDNA array, (2) to develop a genetic prognostic model for ovarian cancer utilizing the data from patients entered on Gynecologic Oncology Group (GOG) protocol 9404 by correlating cDNA array data with clinical end points such as tumor site, histological subtype and grade, chemoresponse, and long-term survival, and (3) to identify and validate candidate genes with prognostic values by fluorescence in situ hybridization (FISH), quantitative PCR, and immunohistochemistry. The correlation study on CNA profiles and clinical outcome data will not only provide insights into the biological basis of the prognostic associations, but also identify prognostic markers for stratifying patients in future clinical trials to assess the role of chemotherapy in the treatment of ovarian cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
1R33CA103595-01
Application #
6695870
Study Section
Special Emphasis Panel (ZCA1-SRRB-3 (M1))
Program Officer
Lively, Tracy (LUGO)
Project Start
2003-08-26
Project End
2007-07-31
Budget Start
2003-08-26
Budget End
2004-07-31
Support Year
1
Fiscal Year
2003
Total Cost
$454,147
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Ghosh, Sue; Albitar, Lina; LeBaron, Richard et al. (2010) Up-regulation of stromal versican expression in advanced stage serous ovarian cancer. Gynecol Oncol 119:114-20
Kwong, Joseph; Chan, Franky Leung; Wong, Kwong-kwok et al. (2009) Inflammatory cytokine tumor necrosis factor alpha confers precancerous phenotype in an organoid model of normal human ovarian surface epithelial cells. Neoplasia 11:529-41
Mok, Samuel C; Bonome, Tomas; Vathipadiekal, Vinod et al. (2009) A gene signature predictive for outcome in advanced ovarian cancer identifies a survival factor: microfibril-associated glycoprotein 2. Cancer Cell 16:521-32
Nevadunsky, Nicole S; Barbieri, John S; Kwong, Joseph et al. (2009) RUNX3 protein is overexpressed in human epithelial ovarian cancer. Gynecol Oncol 112:325-30
Callahan, Michael J; Nagymanyoki, Zoltan; Bonome, Tomas et al. (2008) Increased HLA-DMB expression in the tumor epithelium is associated with increased CTL infiltration and improved prognosis in advanced-stage serous ovarian cancer. Clin Cancer Res 14:7667-73
Cheung, Kwok-Kuen; Mok, Samuel C; Rezaie, Payam et al. (2008) Dynamic expression of Dab2 in the mouse embryonic central nervous system. BMC Dev Biol 8:76
Litkouhi, Behrang; Litkouhi, Babak; Fleming, Evelyn et al. (2008) Overexpression of CEACAM6 in borderline and invasive mucinous ovarian neoplasms. Gynecol Oncol 109:234-9
Koon, E C; Ma, P C; Salgia, R et al. (2008) Effect of a c-Met-specific, ATP-competitive small-molecule inhibitor SU11274 on human ovarian carcinoma cell growth, motility, and invasion. Int J Gynecol Cancer 18:976-84
Gagnon, Audrey; Kim, Jae-Hoon; Schorge, John O et al. (2008) Use of a combination of approaches to identify and validate relevant tumor-associated antigens and their corresponding autoantibodies in ovarian cancer patients. Clin Cancer Res 14:764-71
Park, Dong Choon; Yeo, Seung Geun; Wilson, Mark R et al. (2008) Clusterin interacts with Paclitaxel and confer Paclitaxel resistance in ovarian cancer. Neoplasia 10:964-72

Showing the most recent 10 out of 28 publications