The Role of Inflammation in the Racial Disparities in Ovarian Cancer Survival

摘要 这份申请将为应聘者佩雷斯博士提供必要的职业发展和研究 作为一名独立的分子癌症流行病学家，她的经历推动了她的事业。佩雷斯博士的长期 职业目标是将癌症流行病学和分子生物学领域结合起来，以理清 分子和环境危险因素对癌症病因和预后的独立和联合作用 并特别强调这些因素如何影响健康差距。卵巢上皮癌(EOC)是 美国最致命的妇科恶性肿瘤和非裔美国人(AA)女性的 与欧洲血统的妇女(EA)的预后进行比较。促成这一生存的因素 差异是相对未知的，由于AA数量较少，这一领域的研究还处于起步阶段 妇女在现有的EoC流行病学研究中的作用。考虑到慢性炎症和 EOC的病因和预后，加上观察到的RACE炎症生物标志物的差异，我们 假设炎症的差异可能是再生障碍性贫血女性EOC生存差距的原因之一。建议数 这项研究将利用现有的两项基于人群的病例对照研究，即非裔美国人癌症 流行病学研究(AACES)和北卡罗来纳州卵巢癌研究(NCOCS)，以评估 全身炎症和局部炎症在肿瘤微环境影响中的独立和联合作用 再生障碍性贫血患者的卵巢上皮性癌预后以及这些炎性生物标志物的差异是否起作用 平等机会委员会中的种族生存差距。白细胞类型和分布将作为系统性疾病的标志物 和局部炎症。诊断时将从全血细胞计数中获取循环白细胞 以及确诊后采集的外周血样。从外周血中推断出白细胞比例 血液DNA甲基化数据(光甲基化EPIC珠片)使用细胞混合物去卷积方法。 为了测量局部炎症，我们将使用免疫组织化学来获得肿瘤浸润性计数。 原发肿瘤内淋巴细胞(FOXP3、CD3、CD8)和中性粒细胞(CD66b)，并测定Klintrup Score，肿瘤和每种白细胞类型内的总体炎症的通用标志。最后，我们 将评估与炎症相关的暴露(例如，肥胖、止痛药使用、生殖器身体 粉尘暴露)导致全身和/或局部炎症，以及这些生物标志物是否 炎性暴露与卵巢上皮性癌生存关系的介体。为了实现 在拟议的研究目标下，佩雷斯博士将获得癌症表观遗传学、分子生物学等方面的额外知识 生物学和生物信息学通过她的培训和职业发展活动以及指导 由她的跨学科咨询委员会提供。拟议的研究将提高我们对 导致再生障碍性贫血妇女EoC存活率较低的因素，并可能对 我们的首要目标是减少平等机会委员会现有的种族生存差距。

ABSTRACT This application will provide the candidate, Dr. Peres, with the necessary career development and research experiences to propel her career as an independent molecular cancer epidemiologist. Dr. Peres’ long-term career goal is to integrate the fields of cancer epidemiology and molecular biology to disentangle the independent and joint effects of molecular and environmental risk factors on cancer etiology and prognosis, with a special emphasis on how these factors influence health disparities. Epithelial ovarian cancer (EOC) is the deadliest gynecologic malignancy in the U.S. and African American (AA) women have a much poorer prognosis in comparison to women of European ancestry (EA). The contributing factors to this survival disparity are relatively unknown, and research in this area is in its infancy due to the small numbers of AA women in existing epidemiologic studies on EOC. Given the suggested link between chronic inflammation and EOC etiology and prognosis coupled with the observed differences in biomarkers of inflammation by race, we posit that differences in inflammation may be contributing to the EOC survival gap in AA women. The proposed research will capitalize on two existing population-based case-control studies, the African American Cancer Epidemiology Study (AACES) and the North Carolina Ovarian Cancer Study (NCOCS), to evaluate how the independent and joint effects of systemic and local inflammation in the tumor microenvironment influences EOC prognosis among AA women and whether differences in these inflammatory biomarkers are contributing to the racial survival disparity in EOC. Leukocyte cell type and distribution will be used as markers of systemic and local inflammation. Circulating leukocytes will be obtained from the complete blood cell count at diagnosis and a peripheral blood sample obtained after diagnosis. Leukocyte proportions will be inferred from peripheral blood DNA methylation data (Illumina MethylationEPIC BeadChip) using cell mixture deconvolution methods. To measure local inflammation, we will use immunohistochemistry to obtain counts of tumor-infiltrating lymphocytes (FOXP3, CD3, CD8) and neutrophils (CD66b) within the primary tumor and measure the Klintrup score, a general marker of overall inflammation with the tumor and within each leukocyte cell type. Lastly, we will evaluate whether inflammatory-related exposures (e.g., obesity, analgesic medication use, genital body powder exposure) contribute to systemic and/or local inflammation, and whether these biomarkers are mediators of the relationship between inflammatory-related exposures and EOC survival. In order to achieve the proposed research objectives, Dr. Peres will obtain additional knowledge in cancer epigenetics, molecular biology and bioinformatics through her training and career development activities as well as the mentoring provided by her interdisciplinary advisory committee. The proposed research will improve our understanding of the contributing factors to poor EOC survival among AA women and will likely have a considerable impact on our over-arching goal of reducing the existing racial survival disparity in EOC.