The candidate is a gynecologic oncologist with a commitment to a career in basic science and translational research. The University of Washington has a strong clinical cancer program, an established gynecologic cancer tissue bank, and a renowned research program in genomics and medical genetics. Under the guidance of Mary-Claire King, Ph.D., the candidate will use these institutional resources to gain advanced training in genetics laboratory research while completing the proposed project. She will participate in the didactic activities for fellows in the Division of Medical Genetics. Ovarian cancer has the highest mortality among gynecologic cancers, and current screening strategies are inadequate for application to the general population. This study will pursue the goal of identifying novel molecular markers in ovarian cancer using two strategies: 1. A gene-based strategy based on the hypothesis that BRCA1 is important in the development of sporadic ovarian cancer and that BRCA1 and related genes are aberrantly regulated early in the development of ovarian cancer. 2. A marker-based strategy based on the hypothesis that tumor-specific changes identified in mitochondrial or nuclear DNA are identifiable in DNA obtained from peritoneal fluid or from patient sera or plasma and can be used as prognostic or diagnostic tools. In both strategies, molecular findings will be correlated to clinical variables and patient outcomes to identify those molecular markers with potential utility as a prognostic or diagnostic tool.
Specific Aim 1. In ovarian cancers, evaluate expression of BRCA1 and other proteins that may interact with BRCA1 including Id4, CTCF, and ATM, correlating protein expression with clinical outcomes in both hereditary and sporadic ovarian cancer.
Specific Aim 2. Evaluate promoter methylation of genes in ovarian cancer including BRCA1, MLH1, THBS1, CDH1, Cyclin D2, ERalpha and ERbeta. Assess tumor-specific methylation in DNA from patient sera, plasma and peritoneal fluid, correlating these findings with clinical variables and outcomes.
Specific Aim 3. Identify the frequency of mitochondrial mutations or variants in ovarian cancers in comparison to matched normal DNA. Assess tumor-specific mitochondrial mutations in DNA from patient sera or plasma and peritoneal fluid, and correlate the presence of the mutations with clinical outcomes. Preliminary data indicate the feasibility of all three specific alms. These studies may identify new prognostic or diagnostic markers in ovarian cancer. Such markers could then be tested in prospective trials to determine their clinical utility.
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