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Background  Prognostic tools for prostate cancer (PC) are inadequate and new molecular biomarkers may improve risk stratification. The epigenetic mark 5-hydroxymethylcytosine (5hmC) has recently been proposed as a novel candidate prognostic biomarker in several malignancies including PC. 5hmC is an oxidized derivative of 5-methylcytosine (5mC) and can be further oxidized to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). The present study is the first to investigate the biomarker potential in PC for all four DNA methylation marks in parallel. Thus, we determined 5mC, 5hmC, 5fC, and 5caC levels in non-malignant (NM) and PC tissue samples from a large radical prostatectomy (RP) patient cohort ( n  = 546) by immunohistochemical (IHC) analysis of serial sections of a tissue microarray. Possible associations between methylation marks, routine clinicopathological parameters,  ERG  status, and biochemical recurrence (BCR) after RP were investigated.    Results  5mC and 5hmC levels were significantly reduced in PC compared to NM prostate tissue samples ( p  ≤ 0.027) due to a global loss of both marks specifically in  ERG−  PCs. 5fC levels were significantly increased in  ERG+  PCs ( p  = 0.004), whereas 5caC levels were elevated in both  ERG−  and  ERG+  PCs compared with NM prostate tissue samples ( p  ≤ 0.019). Positive correlations were observed between 5mC, 5fC, and 5caC levels in both NM and PC tissues ( p  < 0.001), while 5hmC levels were only weakly positively correlated to 5mC in the PC subset ( p  = 0.030). There were no significant associations between 5mC, 5fC, or  ERG  status and time to BCR in this RP cohort. In contrast, high 5hmC levels were associated with BCR in  ERG−  PCs ( p  = 0.043), while high 5caC levels were associated with favorable prognosis in  ERG+  PCs ( p  = 0.011) and were borderline significantly associated with worse prognosis in  ERG−  PCs ( p  = 0.058). Moreover, a combined high-5hmC/high-5caC score was a significant adverse predictor of post-operative BCR beyond routine clinicopathological variables in  ERG−  PCs (hazard ratio 3.18 (1.54–6.56),  p  = 0.002, multivariate Cox regression).    Conclusions  This is the first comprehensive study of 5mC, 5hmC, 5fC, and 5caC levels in PC and the first report of a significant prognostic potential for 5caC in PC.    Electronic supplementary material  The online version of this article (10.1186/s13148-018-0540-x) contains supplementary material, which is available to authorized users.

clinical epigenetics

Dysregulation and prognostic potential of 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) levels in prostate cancer