Abstract
The molecular diversity of prostate cancer (PCa) has been demonstrated by recent genome-wide studies, proposing a significant number of different molecular markers. However, only a few of them have been transferred into clinical practice so far. The present study aimed to identify and validate novel DNA methylation biomarkers for PCa diagnosis and prognosis. Microarray-based methylome data of well-characterized cancerous and noncancerous prostate tissue (NPT) pairs was used for the initial screening. Ten protein-coding genes were selected for validation in a set of 151 PCa, 51 NPT, as well as 17 benign prostatic hyperplasia samples. The Prostate Cancer Dataset (PRAD) of The Cancer Genome Atlas (TCGA) was utilized for independent validation of our findings. Methylation frequencies of ADAMTS12, CCDC181, FILIP1L, NAALAD2, PRKCB, and ZMIZ1 were up to 91% in our study. PCa specific methylation of ADAMTS12, CCDC181, NAALAD2, and PRKCB was demonstrated by qualitative and quantitative means (all p < 0.05). In agreement with PRAD, promoter methylation of these four genes was associated with the transcript down-regulation in the Lithuanian cohort (all p < 0.05). Methylation of ADAMTS12, NAALAD2, and PRKCB was independently predictive for biochemical disease recurrence, while NAALAD2 and PRKCB increased the prognostic power of multivariate models (all p < 0.01). The present study identified methylation of ADAMTS12, NAALAD2, and PRKCB as novel diagnostic and prognostic PCa biomarkers that might guide treatment decisions in clinical practice.
Highlights
Despite tremendous improvements in diagnostics and treatment tactics, prostate cancer (PCa) is the second most common malignancy among men and the leading cause of cancer-related death among all urogenital cancers [1]
After introducing aggressive prostate-specific antigen (PSA) testing into clinical practice, the diagnosis of PCa has dramatically shifted towards the early stage and localized disease [2]
Methylation of promoter region has been reported to be responsible for silencing more than 100 PCa genes, where glutathione Stransferase pi 1 (GSTP1) and RAS association domain family member 1 (RASSF1) has been the most intensively analyzed [4]
Summary
Despite tremendous improvements in diagnostics and treatment tactics, prostate cancer (PCa) is the second most common malignancy among men and the leading cause of cancer-related death among all urogenital cancers [1]. Limited PSA prognostic power has increased the detection of clinically insignificant disease, leading to over-treatment with a huge negative impact on males’ physical and mental well-being [3]. All these drawbacks encouraged the search for new diagnostic and prognostic PCa biomarkers with better performance characteristics. Scientific evidence about prognostic DNA methylation biomarkers remains scarce as most investigations have resulted in ambiguous data. Most of these studies have focused on comparing cancerous with noncancerous prostate tissue (NPT)
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