Genetic and Epigenetic Markers in Ovarian Cancer

描述（由申请人提供）：候选人是一名致力于基础科学和转化研究的妇科肿瘤学家。华盛顿大学有一个强大的临床癌症项目，一个建立的妇科癌症组织库，以及一个著名的基因组学和医学遗传学研究项目。在Mary-Claire King博士的指导下，候选人将利用这些机构资源获得遗传学实验室研究方面的高级培训，同时完成拟议的项目。她将参加医学遗传学部的教学活动。卵巢癌在妇科癌症中死亡率最高，目前的筛查策略不足以应用于一般人群。本研究将采用两种策略来确定卵巢癌的新分子标志物：1。基于BRCA1在散发性卵巢癌的发展中起重要作用以及BRCA1及相关基因在卵巢癌发展早期异常调控的假设的基于基因的策略。2. 一种基于标志物的策略，假设线粒体或核DNA中发现的肿瘤特异性变化可在从腹膜液或患者血清或血浆中获得的DNA中发现，可作为预后或诊断工具。在这两种策略中，分子发现将与临床变量和患者结果相关联，以确定那些具有潜在效用的分子标记，作为预后或诊断工具。

DESCRIPTION (provided by applicant): 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.