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.
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