Abstract 5318: High-grade serous ovarian cancer DNA methylation and survival in African-American women
Authors: Salas Lucas A. , Peres Lauren C. , Abbott Sarah E. , Greene Casey S. , Marks Jeffrey R. , Alberg Anthony J. , Bandera Elisa V. , Barnholtz-Sloan Jill S. , Schwartz Ann G. , Cote Michele L. , Moorman Patricia G. , Funkhouser Ellen M. , Peters Edward S. , Bondy Melissa L. , Terry Paul D. , Doherty Jennifer A. , Christensen Brock C. , Schildkraut Joellen M. 
Published: August 2018

Ovarian cancer is the most lethal gynecologic cancer in the United States, and African-American (AA) women have the poorest outcomes compared to other racial/ethnic groups. Although several biomarkers have been proposed to establish prognosis in European ancestry (EA) patients, including some DNA methylation markers (FGF4, FGF21, MYLK2, MYLK3, MYL7, and ITGAE) (Phelps et al., 2017), it is unknown if these or other markers are applicable to AA patients. Using data from the African-American Cancer Epidemiology Study (AACES), we evaluated 1) if DNA methylation is associated with residual disease and survival, and 2) if previously reported CpG biomarkers for EA women are related to survival in AA women. 121 AA women with high-grade serous ovarian cancer (HGSOC) were randomly selected from 600 women enrolled in AACES. Clinical records and formalin-fixed, paraffin-embedded (FFPE) tumor tissue were retrieved, and a pathologist reviewed histopathologic slides to confirm diagnosis. 92 HGSOC had complete clinical information. DNA methylation was measured using Illlumina HumanMethylationEPIC. Beta-values were preprocessed (RELIC, Tost+BMIQ and ComBat). Low quality probes were filtered. Tumor purity was estimated using InfiniumPurify; &lt;30% was considered low purity. Four cell estimates (RefFreecellmix) were used as a proxy of cell composition. To evaluate DNA methylation alterations, we used the top 100K most variable CpG sites and a semisupervised recursively partitioned mixture model (ssRPMM) approach to delineate the patients into RPMM classes. We also evaluated the six candidate CpGs from Phelps et al. The dataset was divided into training and validation subsets (50% each); if findings were consistent, a pooled statistic is reported. We used logistic regression to evaluate the association between DNA methylation and residual disease; Cox proportional hazard models were used for survival. Models were adjusted for age at diagnosis, low purity, cell types, neoadjuvant therapy, tissue source (adnexa vs. peritoneum), histology (serous vs. mixed), and residual disease. The RPMM classes were not associated with residual disease. For survival, four RPMM classes were delineated, which we collapsed into two classes. A lower risk of mortality was observed for one of the RPMM classes, HR: 0. 03[95% CI: 0.01-0.12]. This “low risk” RPMM class grouped five CpGs in genes PLEC1, AP5B1, DNAH7 and MAPK15. These genes have been associated with cell motility and ovarian cancer ascites. Among the candidate CpGs, we only observed a trend to better survival per every 10% increase in MYLK3 CpG methylation, HR: 0.51 [95%CI: 0.24-1.10]. These preliminary results suggest that some DNA methylation modifications may identify subgroups of AA women with better survival. Previously reported biomarkers in EA may not be as useful in AA women. Future studies with increased sample size may help to disentangle these associations.

Citation Format: Lucas A. Salas, Lauren C. Peres, Sarah E. Abbott, Casey S. Greene, Jeffrey R. Marks, Anthony J. Alberg, Elisa V. Bandera, Jill S. Barnholtz-Sloan, Ann G. Schwartz, Michele L. Cote, Patricia G. Moorman, Ellen M. Funkhouser, Edward S. Peters, Melissa L. Bondy, Paul D. Terry, Jennifer A. Doherty, Brock C. Christensen, Joellen M. Schildkraut. High-grade serous ovarian cancer DNA methylation and survival in African-American women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5318.