Search

Global DNA methylation may affect chromosome structure and genomic stability and is involved in carcinogenesis. In this study, we aimed to investigate whether methylation of pericentromeric repeat NBL2 and subtelomeric repeat D4Z4 in peripheral blood was associated with the aggressiveness of prostate cancer (PCa). We measured the methylation status of different CpG sites of NBL2 and D4Z4 in 795 PCa patients and compared their methylation levels among patients with different Gleason Score at diagnosis. We then analyzed the association of the NBL2 and D4Z4 methylation with the risk of biochemical recurrence (BCR) in patients receiving radical prostatectomy or radiotherapy 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. There was no significant difference in methylation level of NBL2 and D4Z4 between clinically defined aggressive and non-aggressive PCa at diagnosis. However, the methylation of D4Z4 was associated with BCR, while the methylation of NBL2 was not. In tertile analysis, patients in the highest tertile of D4Z4 methylation had an increased risk of BCR (HR = 2.17, 95% CI 1.36-3.48) compared to patients in the lower tertiles after adjustment of age, body mass index, smoking status, pack year, D'Amico risk groups and treatments. Among the four CpG sites in this region, the association was mostly attributable to the methylation of the second CpG site of D4Z4. These data suggest that higher methylation in D4Z4 was associated with worse prognosis of localized PCa patients.

Mitochondria play multiple important cellular functions. The purpose of this study was to evaluate whether leukocyte mitochondrial DNA copy number (mtDNAcn) is associated with aggressive prostate cancer (PCa) in African American (AA) men. We measured the mtDNAcn in peripheral blood leukocytes from 317 localized AA PCa patients and evaluated its associations with aggressive disease features at diagnosis and biochemical recurrence (BCR) after treatments. There was no significant difference in mtDNAcn among the clinical features at diagnosis, including age, prostate-specific antigen level, Gleason score and clinical stage under analysis of variance test. However, mtDNAcn was significantly associated with BCR in multivariate Cox analysis. Dichotomized into low and high mtDNAcn groups by the median value of mtDNAcn, patients with low mtDNAcn exhibited a significantly lower risk of BCR (hazard ratio = 0.32, 95% confidence interval: 0.13–0.79) compared to those with high mtDNAcn. There was a significant dose–response in tertile and quartile analyses (P for trend = 0.012 and 0.002, respectively). In Kaplan–Meier survival analyses, patients with higher mtDNAcn exhibited significantly shorter BCR-free survival time than those with lower mtDNAcn in dichotomous, tertile and quartile analyses, with long-rank P values of 0.017, 0.024 and 0.019, respectively. Our results showed for the first time that high leukocyte mtDNAcn was associated with worse prognosis in AA PCa patients.

Global DNA methylation may play important roles in cancer etiology and prognosis. The goal of this study is to investigate whether the methylation of long interspersed nucleotide elements (LINE-1) and subtelomeric DNA repeats D4Z4 in leukocyte DNA is associated with aggressive prostate cancer (PCa) in African Americans. We measured DNA methylation levels of LINE-1 and D4Z4 in 306 African American (AA) PCa patients using pyrosequencing and compared their methylation levels among clinical variables. We further applied multivariate Cox proportional hazards model and Kaplan–Meier survival function and log-rank tests to assess the association between DNA methylation and biochemical recurrence (BCR). Overall, there was no significant difference of the methylation levels of LINE-1 and D4Z4 among patients with different clinical and epidemiological characteristics. However, the methylation of LINE-1 and D4Z4 was associated with BCR. Patients with lower LINE-1 methylation and higher D4Z4 methylation exhibited markedly increased risks of BCR with adjusted hazard ratios of 3.34 (95% confidence interval, 1.32–8.45) and 4.12 (95% confidence interval, 1.32–12.86), respectively, and significantly shorter BCR-free survival times. Our results suggest that lower global DNA methylation and higher subtelomeric region methylation may predict worse prognosis in localized AA PCa patients.