| Abstract [eng] |
Prostate cancer (PCa) is the most common cancer in men and the second leading cause of male deaths in Europe. Several recent studies have suggested an association between promoter hypermethylation of hypoxia and angiogenesis-related genes and development of various types of cancer including PCa. Identification of new potential epigenetic biomarkers could greatly enhance our ability to diagnose PCa in the early stages and to predict the course of the disease after the surgery. The aim of our study - was to investigate with qualitative method methylation profile of ADAMTS12, FILIP1L and EPAS1 that were selected according to the DNA methylation microarrays analysis and evaluate the diagnostic and prognostic value of the selected epigenetic markers for PCa detection. Total epigenome analysis of prostate tumors using DNA methylation microarrays technology allowed the identification of genes associated with angiogenesis and hypoxia ADAMTS12, FILIP1L, and EPAS1 which are characterized by DNA methylation changes in tumors. Methylation status of regulatory and promoter sequences of selected genes was validated in 129 PCa and 30 benign prostate (NPT) samples by methylation-specific PCR (MSP). As an additional control group were used 17 benign prostate hyperplasia (BPH) samples. ADAMTS12 and FILIP1L promoter methylation was detected in 109 of 129 (84%) PCa samples for each gene. In NPT, methylation frequencies of ADAMTS12 and FILIP1L were 6% (2 of 35) and 11% (4 of 35), respectively and the difference was statistically significant versus PCa (P < 0.001) cases. No methylation changes were observed in BPH samples. EPAS1 gene was unmethylated in all analyzed PCa and NPT samples. Methylation of ADAMTS12 gene promoter was significantly associated with biochemical disease recurrence (P = 0.006) and was frequently observed in higher tumor stage (P = 0.071) and in higher Gleason score (P = 0.098) cases of evaluated tumors. No statistically significant correlations were observed between ADAMTS12 or FILIP1L methylation status and prostate-specific antigen (PSA) level, prostate mass, or patients’ age. Our study revealed a significant difference in methylation frequencies of the ADAMTS12 and FILIP1L genes between prostate tumor and non-tumor tissues and BPH, and potential prognostic significance of ADAMTS12 gene promoter‘s methylation. Quantitative genes’ expression analysis will allow a more accurate assessment of sensitivity and specificity of these genes as molecular markers in PCa. |
