Project 02: Tumor Methylomics Analysis Link with Racial Disparities in Ovarian Cancer

摘要： 卵巢癌（OC）仍然是最致命的妇科癌症和最近的癌症登记为基础的分析， 据报道，与白色（W）相比，非洲裔美国人（AA）妇女的生存率显著降低 卵巢癌患者，尽管诊断时的分期分布和组织学类型相似。这种差异 可以通过获得医疗保健和其他社会经济因素的差异来解释，但也可以通过 可能影响治疗反应的生物学特征差异。知之甚少 OC差异的种族定义的生物学关键决定因素的差异以及研究这些差异的适当模型 差异尚不可用。在此，我们建议开始解决这一未满足的需求，重点是 表观遗传因素，特别是DNA甲基化，我们假设它是社会- 经济或环境因素和基因组改变来改变疾病进程和对治疗的反应。 卵巢癌中DNA甲基化事件的种族差异尚未确定。另一个未得到满足的 需要开发适当的临床前模型（类器官，患者来源的异种移植物）， 用于测量对治疗的反应，这将反映AA与白色女性相比OC的独特生物学特性。到 为了解决这些问题，我们提出了两个目标，这两个目标将被纳入更大的范围， SPORE应用程序解决妇科癌症的差异，并将利用我们的专业知识， DNA甲基化和OC的临床前治疗测试。在具体目标1中，我们建议将 使用Lurie的组织资源在AA和白色患者中高级别浆液性OC的甲基化组 癌症中心和附属斯特罗格医院，服务于大芝加哥都市区，包括一个 AA女性比例较高。为了实现这一目标，我们将使用Infinium HumanMethylation 950 BeadChip 我们将通过焦磷酸测序验证CpG岛甲基化的关键差异。对于具体目标2，我们 将开始开发高级别浆液性卵巢癌患者来源的异种移植物（PDX）， AA和白色女性的类器官，我们将评估这些模型在体外和体内对铂的反应。 vivo. RNA测序和DNA甲基化阵列将提供整合的基因表达和甲基化组 与来自AA和白色女性的模型的治疗反应相关的特征。在 完成这个项目后，我们将确定在肿瘤中表观遗传调控的关键致癌驱动因素， 从AA与白色妇女，我们将产生有用的新资源，继续解决 与OC对治疗反应的种族差异相关的生物学问题。

Abstract: Ovarian cancer (OC) remains the deadliest gynecologic cancer and recent cancer registry-based analyses reported significantly reduced survival rates among African American (AA) women compared to white (W) women with ovarian cancer, despite similar stage distribution and histological types at diagnosis. This disparity could be accounted for by differences in access to medical care and other socioeconomic factors, but also by differences in biological characteristics which may impact response to treatment. Little is known about differences in racially-defined biological key determinants of OC disparity and adequate models to study these differences are not yet available. Here we propose to begin addressing this unmet need by focusing on epigenetic factors, particularly on DNA methylation, which we hypothesize functions as a link between socio- economic or environmental factors and genomic alterations to modify disease course and response to therapy. Racial differences in DNA methylation events in ovarian cancer have not been yet defined. An additional unmet need is the development of adequate preclinical models (organoids, patient-derived xenografts) that could be used to measure response to treatment and that will reflect the unique biology of OC in AA vs. white women. To address these questions, we propose two aims, which will be integrated into the larger scope of this pre- SPORE application addressing disparities in gynecologic cancer and which will leverage our expertise on DNA methylation and preclinical therapeutic testing in OC. In specific aim 1, we propose to define the methylome of high-grade serous OC in AA and white patients by using tissue resources from the Lurie Cancer Center and affiliated Stroger Hospital, which serve the greater Chicago metropolitan area, including a high proportion of AA women. To accomplish this goal, we will use the Infinium HumanMethylation950 BeadChip array and we will validate key differences in CpG island methylation by pyrosequencing. For specific aim 2, we will begin developing high-grade serous ovarian cancer-derived patient derived xenografts (PDX) and organoids from AA and white women and we will assess response of these models to platinum in vitro and in vivo. RNA-sequencing and DNA methylation arrays will provide integrative gene expression and methylome signatures associated with response to treatment for models derived from AA and white women. At the completion of this project, we would have identified key oncogenic drivers regulated epigenetically in tumors from AA vs. white women and we would have generated useful new resources to continue to address biological questions related to racial differences in OC response to treatment.