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.
The proposed research is relevant to public health because it will reveal critical molecular insights into the mechanisms governing disease progression and response to treatment in ovarian cancer accounting for racial disparities in clinical outcomes. We hypothesize that differences in DNA methylation in ovarian tumors from black vs. white women are responsible for the silencing of key genes implicated in chemotherapy responsiveness and tumor suppression and leading to different biological features of ovarian tumors in these patient populations. Therefore, the proposed research is relevant to NCI?s mission of supporting cancer research to advance scientific knowledge and help all people live longer, healthier lives.
