Methylation of subtelomeric repeat D4Z4 in peripheral blood leukocytes is associated with biochemical recurrence in localized prostate cancer patients

Abstract

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.

The Alteration of Subtelomeric DNA Methylation in Aging-Related Diseases

“…In prostate cancer, hypermethylation of the subtelomeric region D4Z4 was found to be associated with the worse prognosis of the patients (Han et al, 2017). We hypothesize that subtelomeric DNA methylation may be a potential biomarker for tumor prognosis, and more experiments should be performed to validate this conjecture.…”

Epigenome-Wide Association Study of Prostate Cancer in African Americans Identifies DNA Methylation Biomarkers for Aggressive Disease

“…A commercially available test, ConfirmMDx, which measures CpG island methylation of GSTP1, RASSF1, and APC in histopathologically negative prostate core biopsies, has been used clinically to predict PCa and high-grade PCa in repeat biopsies [ 10 , 11 , 12 ]. In addition to DNA methylation in tumor tissues, DNA methylation in peripheral blood leukocytes has also attracted great interest as a predictor of cancer risks and outcomes [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. Recent studies have applied an epigenome-wide association study (EWAS) approach using Illumina’s high-density methylation arrays to identify specific CpG sites in leukocyte DNA that are differentially methylated between European ancestry PCa cases and controls, as well as between low-grade and high-grade PCa patients [ 21 , 22 , 23 ].…”

Ageing affects subtelomeric DNA methylation in blood cells from a large European population enrolled in the MARK-AGE study

“…Alzheimer's disease and Parkinson's disease) [19][20][21][22], metabolic disorders (i.e. diabetes) [23] and some sporadic malignancies [7,[24][25][26][27][28]. Since these diseases are typically associated with ageing, these observations have led to the hypothesis that alterations in the status of subtelomeric methylation might be related to the ageing process.…”