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

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.