Abstract
BackgroundPrognostic 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.Results5mC 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).ConclusionsThis 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.
Highlights
Prognostic tools for prostate cancer (PC) are inadequate and new molecular biomarkers may improve risk stratification
The reduction in 5mC levels was specific for ETS-related transcription factor gene (ERG) − PCs (p < 0.001; chi2 test; Fig. 5a), while 5mC levels were similar in ERG+ PCs and NM samples (p = 0.360; chi2 test; Fig. 5a)
We found that 5fC levels were significantly increased in ERG+ PCs, whereas 5caC levels were significantly elevated in both ERG+ and ERG− PCs, as compared to NM prostate tissue samples
Summary
Prognostic tools for prostate cancer (PC) are inadequate and new molecular biomarkers may improve risk stratification. The present study is the first to investigate the biomarker potential in PC for all four DNA methylation marks in parallel. 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. Novel prognostic biomarkers are needed to accurately identify aggressive PCs and focus active treatment (radical prostatectomy, RP) towards these patients, while avoiding unnecessary surgery and treatmentassociated side effects in men with indolent PC. Several studies have investigated the prognostic value of TMPRSS2:ERG fusion status in early stage PC, but have shown conflicting results [4, 5]. DNA methylation changes have shown promising prognostic potential [6,7,8]
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