Abstract 834: Epigenome-wide profiling of DNA methylation in peripheral blood leukocytes and the prognosis of prostate cancer patients in African Americans

Abstract

Abstract Introduction: DNA methylation at CpG sites plays important roles in cancer development and progression. Hypermethylation of the promoter regions of tumor suppressor genes leads to gene silencing whereas global hypomethylation may affect chromosome structure and cause genomic instability. African Americans have higher incidence and mortality rates of prostate cancer than other ethnic groups. The goals of this study are to investigate the role of global DNA methylation in prostate cancer aggressiveness and identify CpG site methylations as predictors of aggressive prostate cancer in African Americans. Methods: We measured global DNA methylation level of long interspersed nucleotide elements (LINE-1) and subtelomeric repeat (D4Z4) in leukocyte DNA from ~300 African American prostate cancer patients and compared their methylation levels between different clinicopathological variables at diagnosis. We then analyzed the association of the LINE-1 and D4Z4 methylation with the risk of biochemical recurrence (BCR) using a multivariate Cox proportional hazards model. In addition, we used the Kaplan-Meier survival function and log-rank tests to assess BCR-free survival associated with D4Z4 methylation.. We also used Illumina’s HumanMethylationEPIC beadchip to profile 850K CpG site methylation in leukocytes and analzyed their associations with prostate cancer aggressiveness. Results: There was no significant differences in the methylation level of LINE-1 between clinically defined aggressive and non-aggressive PCa at diagnosis and LINE-1 methylation was not associated with BCR either. However, the methylation of subtelomeric region D4Z4 was associated with BCR. Patients with higher methylation of D4Z4 exhibited an increased risk of BCR (HR=3.47, 95% CI, 1.10 - 10.97) compared to patients in the lower methylation after adjustment of age, BMI, smoking status, pack year, D’Amico risk groups, and treatments. In Kaplan-Meier survival analysis, patients with higher D4Z4 methylation level had a significantly shorter BCR-free survival time than those with lower methylation level (log rank P = 0.0071). When analyzing individua CpG site methylation, we identified a number of CpG site that can distinguish aggressive from non-aggressive prostate cancer and found a CpG methylation signature that can identify a subgroup of patients with aggressive prostate cancer in African Americans. Conclusions: These data suggest that methylation in the subtelomeric region D4Z4 may be able to predict worse prognosis of patients. Individual CpG site methylation may be promising biomarkers for the identification of aggressive prostate cancer in African Americans. Citation Format: Junfeng Xu, Chia-Wen Tsai, Wen-Shin Chang, Da-Tian Bau, Jian Gu. Epigenome-wide profiling of DNA methylation in peripheral blood leukocytes and the prognosis of prostate cancer patients in African Americans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 834.