Genetic and Epigenetic Markers in Ovarian Cancer

描述（由申请人提供）：候选人是一名妇科肿瘤学家，致力于基础科学和转化研究。 华盛顿大学拥有强大的临床癌症项目、成熟的妇科癌症组织库以及著名的基因组学和医学遗传学研究项目。 在玛丽-克莱尔·金博士的指导下，候选人将利用这些机构资源，在完成拟议项目的同时，获得遗传学实验室研究方面的高级培训。 她将参加医学遗传学系研究员的教学活动。 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普通人群。 本研究将采用两种策略来寻找新的卵巢癌分子标志物：1。基于以下假设的基因策略：BRCA1在散发性卵巢癌的发生中很重要，并且BRCA1和相关基因在卵巢癌发生的早期受到异常调节。 2.一种基于标记物的策略，其基于以下假设：在线粒体或核DNA中鉴定的肿瘤特异性变化在从腹膜液或患者血清或血浆中获得的DNA中是可鉴定的，并且可用作预后或诊断工具。 在这两种策略中，分子结果将与临床变量和患者结局相关，以鉴定具有作为预后或诊断工具的潜在效用的分子标记物。 具体目标1。 在卵巢癌中，评估BRCA1和其他可能与BRCA1相互作用的蛋白质（包括Id4、CTCF和ATM）的表达，将蛋白质表达与遗传性和散发性卵巢癌的临床结局相关联。 评估卵巢癌中基因的启动子甲基化，包括BRCA1、MLH1、THBS1、CDH1、Cyclin D2、ER α和ER β。 评估来自患者血清、血浆和腹腔液的DNA中的肿瘤特异性甲基化，将这些发现与临床变量和结果相关联。 与匹配的正常DNA相比，确定卵巢癌中线粒体突变或变异的频率。 评估来自患者血清或血浆和腹膜液的DNA中的肿瘤特异性线粒体突变，并将突变的存在与临床结局相关联。 初步数据表明，所有三个具体的施舍的可行性。 这些研究可能会发现新的卵巢癌预后或诊断标志物。 然后可以在前瞻性试验中测试这些标记物以确定其临床效用。

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.