DESCRIPTION (provided by applicant): Ovarian cancer continues to be the leading cause of death from gynecological malignancies and the fifth most common cancer among US women. The vast majority of patients present with advanced disease at diagnosis, for which survival rates are poor and for which platinum-based combination chemotherapy is indicated. Very few previous ovarian cancer studies focused on genetic polymorphisms and ovarian cancer prognosis. We are unaware of any prior work that employed a comprehensive approach focusing on polymorphic genes related to the metabolism of chemotherapeutic agents, protection from treatment- generated reactive oxygen species (ROS) or DNA damage, and drug resistance. Genetic variability in such key genes that are directly related to the potential effectiveness of chemotherapeutic agents may help to explain the differences in response to treatment and outcomes among ovarian cancer patients. The goal of the proposed study is to build a foundation for a comprehensive pharmacogenetic study of ovarian cancer. We intend to conduct a pilot study aimed at investigating the effect of a panel of candidate polymorphic genes, directly relevant to ovarian cancer chemotherapy, on clinical outcome measures among patients treated at our institute. We further propose to evaluate the appropriateness of using tumor tissue for pharmacogenetic investigations in ovarian cancer by comparing the allele distribution of our candidate genetic polymorphisms in paired DNA samples isolated from tumor tissue and from blood samples. We will utilize patient samples from an ongoing population-based case-control study of ovarian cancer. Specifically, we will include ovarian cancer patients who were treated at Roswell Park Cancer Institute. We have had very encouraging participation and blood donation rates in this study (81% and 97%, respectively) and frozen tumor samples are available for post patents (92%). We will obtain tumor tissue from our Tissue Procurement Facility and use the Genotyping Division of the Microarray and Genomics Facility for genotyping analyses. Clinical outcome information will be collected from medical records review. Results from the proposed study should be a solid foundation for a larger R01 application aimed at investigating pharmacogenetic influences on ovarian cancer prognosis, as results will a) provide preliminary data, and b) will determine if archived tissue banks can be utilized for such research.
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