Genetic Markers Associated with Epithelial Ovarian Cancer and Hypodontia

描述(申请人提供)：上皮性卵巢癌(EOC)，被称为女性的沉默杀手，由于缺乏有效的早期筛查标记物而难以诊断。如果不改进目前的早期检测方案，超过70%的被诊断为EOC的妇女将被发现为晚期疾病，生存机会显著降低。有趣的是，肯塔基大学最近的研究表明，与没有EOC的年龄匹配的对照组受试者相比，被诊断为EOC的受试者也有8.1倍的可能性也有牙齿减少，即缺乏1到6颗恒牙的形成。早在9岁时就可以通过牙科诊所的X光片诊断出的牙缺乏症，可能是目前已知的最早的EOC风险标记。然而，如果在医疗或牙科诊所中仅将牙齿发育不良作为风险标记，许多女性可能会以高昂的成本和焦虑接受更多的EOC测试，可能并不真正处于风险之中。如果能够识别出与患有牙齿发育不良的EOC患者(与健康对照相比)有更多关联的特定标记(人的遗传密码的变化)，这些标记可以用于早期筛查患有牙齿发育不良的年轻女性，以确定女性一生中患上EOC的风险最高。这可能会导致对患EOC风险最高的妇女进行更早的筛查，增加早期诊断的数量，并挽救无数人的生命。这项研究将从肯塔基州中部高加索女性的唾液中创建一个DNA(遗传密码)资源库，这些女性要么被诊断为EOC，要么是健康对照对象。每个受试者的DNA样本将与受试者完整的牙科病史和涵盖三代人的广泛的家族病史/癌症史一起提供。标记(DNA密码的微小变化)将通过一种名为Taqman基因分型的过程进行研究，以确定最常与卵巢早熟和牙齿缺失的受试者有关的标记，而不是对照受试者。待研究的标记位于激活素/抑制素和RUNX细胞间信号通路的基因(DNA代码)中。这两条途径在牙齿发育和生殖组织发育和/或维持中起着重要作用。总而言之，这项研究将确定特定的标志物，结合对女性牙齿发育不足的观察，可能会导致对EOC风险最高的个人进行更早的筛查，增加早期诊断的数量，并挽救许多人的生命。 公共卫生相关性：上皮性卵巢癌(EOC)占女性所有癌症的3%。作为困扰女性的最致命的生殖系统癌症，也是女性因癌症死亡的第五大原因，它是一个重要的健康问题。在所有卵巢癌病例中，只有不到20%的病例是在I期确诊的，当时癌症仅限于卵巢，5年生存率为93%。若不改善现行的早期筛查方法，超过70%被诊断患有平机会的妇女会在癌症转移(即第III期和第IV期)后才获诊断，而5年存活率分别只有34%和18%。这个项目将探索一种新的观察，即缺失的牙齿(从未正确形成的牙齿)似乎与EOC有关。我们将识别基因标记，当这些标记与牙齿缺失的存在相结合时，将识别出在比以前可能的年龄更年轻的一生中患上EOC的风险最大的女性。识别这些高危个体将导致对个体进行更早的筛查，增加早期诊断的数量，并挽救许多人的生命。

DESCRIPTION (provided by applicant): Epithelial ovarian cancer (EOC), known as the silent killer in women, is difficult to diagnosis due to a lack of effective early screening markers for the disease. Without improvements in the current early detection protocols, over 70% of women diagnosed with EOC will be identified in late stage disease with a significantly reduced chance of survival. Interestingly, recent work at the University of Kentucky has demonstrated that subjects diagnosed with EOC were 8.1 times more likely to also have hypodontia, the lack of formation of 1 to 6 permanent teeth, when compared to age-matched control subjects without EOC. Hypodontia, which can be diagnosed as early as age 9 by radiograph in the dental clinic, may be the earliest known marker of EOC- risk today. If hypodontia alone was utilized as a risk marker in the medical or dental clinic, however, many women could undergo increased testing for EOC with great cost and anxiety, and may not truly be at risk. If specific markers (changes in a person's genetic code) could be identified which more frequently associate with EOC patients who have hypodontia (compared to healthy controls) these markers could be utilized for the early screening of young women with hypodontia to identify women at the highest risk for developing EOC in their lifetime. This could lead to earlier screening protocols for women at highest risk of developing EOC, increased numbers of early stage diagnoses, and the saving of countless numbers of lives. This study will create a DNA (genetic code) resource bank from the saliva of a population of Caucasian women in Central Kentucky who have either been diagnosed with EOC or are healthy control subjects. Every subject's DNA sample will be accompanied with the subject's complete dental history and an extensive family medical/cancer history covering three generations. Markers (small changes in the DNA code) will be studies, using a process called Taqman genotyping, to identify markers which most frequently associate with the subjects having EOC and hypodontia but not the control subjects. The markers to be studies are found within genes (DNA code) of the Activin/Inhibin and RUNX cell-to-cell signaling pathways. These two pathways have important roles for tooth development and reproductive tissue development and/or maintenance. In summary, this study will identify specific markers, which when combined with the observation of hypodontia in women, could result in earlier screenings for highest EOC risk individuals, an increase number of early stage diagnoses, and the saving of many lives. PUBLIC HEALTH RELEVANCE: Epithelial Ovarian Cancer (EOC) accounts for 3% of all cancers in women. As the deadliest reproductive system cancer that afflicts women, and the fifth leading cause of death due to cancer in women, it is an important health issue. Less than 20% of all EOC cases are diagnosed in stage I, when the cancer is confined to the ovaries, and the 5 year survival rate is 93%. Without improvements in the current screening methods for early detection, over 70% of women diagnosed with EOC will be diagnosed after the cancer has metastasized (i.e., in Stages III and IV) with 5 year survival rates of only 34% and 18%, respectively. This project will explore the novel observation that missing teeth (teeth that never properly formed) and EOC appear to be associated. We will identify genetic markers, which when combined with the presence of missing teeth, will identify women at greatest risk of developing EOC in their lifetime at much younger ages than previously possible. Identification of these high risk individuals should result in earlier screening regiments for the individuals, an increased number of early stages diagnoses, and the saving of many lives.